Abstract:
Methods for treating leukemia patients include analyzing gene expression profiles of a patient to determine whether the patient is likely to respond to treatment with farnesyl transferase inhibitor (FTI) and, optionally, other therapeutics. The methods are also useful for monitoring patient therapy and for selecting a course of therapy. Genes modulated in response to FTI treatment are provided and are used in formulating the profiles.

Description:
[0001]     This application claims the benefit of the following US applications: US National application Ser. No. 10/283,975 filed Oct. 30, 2002; US Provisional applications 60/340,938 filed Oct. 30, 2001; 60/338,997 filed Oct. 30, 2001; 60/340,081 filed Oct. 30, 2001, and 60/341,012 filed Oct. 30, 2001. This invention relates to diagnostics, prognostics, and treatments for leukemia based on the gene expression profiles of leukemia cells. 
     
    
     BACKGROUND  
       [0002]     Some molecules, such as Ras, that are implicated in cancers must be farnesylated by the farnesyl transferase enzyme in order to interact with the inner leaflet of the plasma membrane of the cell and become involved in various signaling pathways. Ras is not the only protein implicated in cancer that has a CAAX box that is prenylated. Farnesyl transferase inhibitors (FTIs) are therapeutic agents that inhibit the covalent attachment of the carbon farnesyl moieties to the C-terminal CAAX motif of various proteins. They have utility in the treatment of cancers and proliferative disorders such as leukemia. Acute myelogenous leukemia (AML) is among the diseases that can most beneficially be addressed with FTIs.  
         [0003]     As is true in the case of many treatment regimens, some patients respond to treatment with FTIs and others do not. Prescribing the treatment to a patient who is unlikely to respond to it is not desirable. Thus, it would be useful to know how a patient could be expected to respond to such treatment before a drug is administered so that non-responders would not be unnecessarily treated and so that those with the best chance of benefiting from the drug are properly treated and monitored. Further, of those who respond to treatment, there may be varying degrees of response. Treatment with therapeutics other than FTIs or treatment with therapeutics in addition to FTIs may be beneficial for those patients who would not respond to FTIs or in whom response to FTIs alone is less than desired.  
       SUMMARY OF THE INVENTION  
       [0004]     The invention is a method of treating a patient with leukemia with an FTI. In one such method, the patient&#39;s gene expression profile is analyzed to determine whether the patient is likely to respond to the FTI and treating a patient with the FTI if they are likely to respond.  
         [0005]     In another aspect of the invention, a patient with leukemia is monitored for treatment with an FTI in which the patient&#39;s gene expression profile is analyzed to determine whether the patient is responding to the FTI and treating a patient with the FTI if they are likely to respond in a desirable fashion.  
         [0006]     In yet another aspect of the invention, a patient is treated if the gene expression profile shows up regulation of one or more particular genes indicative of FTI responders.  
         [0007]     In yet another aspect of the invention, gene expression profiles indicative of FTI responders are those which show at least a 1.5, 1.7, or 2 fold difference relative to FTI non-responders.  
         [0008]     In yet another aspect of the invention, a patient is treated if the gene expression profile shows down regulation of one or more particular genes indicative of FTI responders  
         [0009]     In yet another aspect of the invention, a patient is treated if the gene expression profile shows modulation of a gene selected from the group of genes identified in Tables 1-3 infra.  
         [0010]     In yet another aspect of the invention, the FTI is a quinilone or quinoline derivative.  
         [0011]     In yet another aspect of the invention, the FTI is (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone).    
         [0012]     Articles used in practicing the methods are also an aspect of the invention. Such articles include gene expression profiles or representations of them that are fixed in computer readable media. Other articles according to the invention include nucleic acid arrays used to determine the gene expression profiles of the invention.  
         [0013]     In another aspect of the invention, a method of treating a patient with leukemia comprises administering an FTI and a therapeutic composition that modulates the MAPK/ERK signaling pathways, TGFβ, WNT or apoptotic pathways.  
         [0014]     In another aspect of the invention, the patient is treated with an FTI and a therapeutic composition selected from the group consisting of tyrosine kinase inhibitors, MEK kinase inhibitors, PI3K kinase inhibitors, MAP kinase inhibitors, apoptosis modulators and combinations thereof.  
         [0015]     In yet another aspect of this invention, the gene expression profile of a patient with leukemia is analyzed to determine whether the patient is likely to respond to an FTI or if the patient would likely benefit from the combination of an FTI and another drug. The patient is then treated with such combination or, if the patient is unlikely to respond to an FTI, the patient is treated with drug selected from the group consisting of tyrosine kinase inhibitors, MEK kinase inhibitors, PI3K kinase inhibitors, MAP kinase inhibitors, apoptosis modulators and combinations thereof. 
     
    
     BRIEF DESCRIPTION OF THE DRAWINGS  
       [0016]      FIG. 1  is an example of a graphical display of gene expression patterns used to analyze the gene expression profiles of this invention.  
         [0017]      FIG. 2  is a schematic diagram of the MAPK/ERK pathway.  
         [0018]      FIG. 3  is a schematic diagram of the TGFβ and Wnt pathway.  
         [0019]      FIG. 4  is a schematic diagram of the apoptotic pathway. 
     
    
     DETAILED DESCRIPTION  
       [0020]     The therapeutic agents referred to in this specification are FTIs. They take on a multitude of forms but share the essential inhibitory function of interfering with or lessening the farnesylation of proteins implicated in cancer and proliferative diseases. Preferably, the FTIs are those indicated for the treatment of leukemias such as AML. A patient who responds to an FTI is one in whom a reduction of more than 50% of blast cells is seen in bone marrow following treatment with the FTI.  
         [0021]     Numerous FTIs are within the scope of the invention and include those described in U.S. Pat. No. 5,976,851 to Brown et al; U.S. Pat. No. 5,972,984 to Anthony et al.; U.S. Pat. No. 5,972,966 to deSolms; U.S. Pat. No. 5,968,965 to Dinsmore et al.; U.S. Pat. No. 5,968,952 to Venet et al.; U.S. Pat. No. 6,187,786 to Venet et al.; U.S. Pat. No. 6,169,096 to Venet et al.; U.S. Pat. No. 6,037,350 to Venet et. al.; U.S. Pat. No. 6,177,432 to Angibaud et al.; U.S. Pat. No. 5,965,578 to Graham et al.; U.S. Pat. No. 5,965,539 to Sebti et al.; U.S. Pat. No. 5,958,939 to Afonso et al.; U.S. Pat. No. 5,939,557 to Anthony et al.; U.S. Pat. No. 5,936,097 to Commercon et al.; U.S. Pat. No. 5,891,889 to Anthony et al.; U.S. Pat. No. 5,889,053 to Baudin et al.; U.S. Pat. No. 5,880,140 to Anthony; U.S. Pat. No. 5,872,135 to deSolms; U.S. Pat. No. 5,869,682 to deSolms; U.S. Pat. No. 5,861,529 to Baudoin; U.S. Pat. No. 5,859,015 to Graham et al.; U.S. Pat. No. 5,856,439 to Clerc; U.S. Pat. No. 5,856,326 to Anthony et al.; U.S. Pat. No. 5,852,010 to Graham et al.; U.S. Pat. No. 5,843,941 to Marsters et al.; U.S. Pat. No. 5,807,852 to Doll; U.S. Pat. No. 5,780,492 to Dinsmore et al.; U.S. Pat. No. 5,773,455 to Dong et al.; U.S. Pat. No. 5,767,274 to Kim et al.; U.S. Pat. No. 5,756,528 to Anthony et al.; U.S. Pat. No. 5,750,567 to Baudoin et al.; U.S. Pat. No. 5,721,236 to Bishop et al,; U.S. Pat. No. 5,700,806 to Doll et al.; U.S. Pat. No. 5,661,161 to Anthony et al.; U.S. Pat. No. 5,602,098 to Sebti et al.; U.S. Pat. No. 5,585,359 to Breslin et al.; U.S. Pat. No. 5,578,629 to Ciccarone et al.; U.S. Pat. No. 5,534,537 to Ciccarone et al.; U.S. Pat. No. 5,532,359 to Marsters et al.; U.S. Pat. No. 5,523,430 to Patel et al.; U.S. Pat. No. 5,504,212 to deSolms et al.; U.S. Pat. No. 5,491,164 to deSolms et al.; U.S. Pat. No. 5,420,245 to Brown et al.; and U.S. Pat. No. 5,238,922 to Graham et al. each of which is incorporated herein by reference. Non-peptidal, so-called “small molecule” therapeutics are preferred. More preferred FTIs are quinolines or quinoline derivatives such as: 
        7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one,     7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,     8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl),methyl]-6-(3-chlorophenyl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, and     8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophenyl)-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one. 
 
 The most preferred FTI is (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone).  
       
 
         [0026]     In the aspect of the invention comprising treating leukemia with FTIs and other therapeutic agents, The therapeutic agents referred to in this specification are those that have an effect on the biological pathway explicated through the gene expression analysis of leukemic cells subjected to treatment with quinilone-based FTIs.  
         [0027]     The mere presence of nucleic acid sequences having the potential to express proteins or peptides (“genes”) within the genome is not determinative of whether a protein or peptide is expressed in a given cell. Whether or not a given gene capable of expressing proteins or peptides does so and to what extent such expression occurs, if at all, is determined by a variety of complex factors. Irrespective of difficulties in understanding and assessing these factors, assaying gene expression can provide useful information about the cellular response to a given stimulus such as the introduction of a drug or other therapeutic agent. Relative indications of the degree to which genes are active or inactive can be found in gene expression profiles. The gene expression profiles of this invention are used to identify and treat patients who will likely benefit from a given therapy or exclude patients from a given therapy where the patient likely would experience little or no beneficial response to the drug or therapy.  
         [0028]     Preferred methods for establishing gene expression profiles (including those used to arrive at the explication of the relevant biological pathways) include determining the amount of RNA that is produced by a gene that can code for a protein or peptide. This is accomplished by reverse transcription PCR (RT-PCR), competitive RT-PCR, real time RT-PCR, differential display RT-PCR, Northern Blot analysis and other related tests. While it is possible to conduct these techniques using individual PCR reactions, it is best to amplify copy DNA (cDNA) or copy RNA (cRNA) produced from mRNA and analyze it via microarray. A number of different array configurations and methods for their production are known to those of skill in the art and are described in U.S. Patents such as: U.S. Pat. Nos. 5,445,934; 5,532,128; 5,556,752; 5,242,974; 5,384,261; 5,405,783; 5,412,087; 5,424,186; 5,429,807; 5,436,327; 5,472,672; 5,527,681; 5,529,756; 5,545,531; 5,554,501; 5,561,071; 5,571,639; 5,593,839; 5,599,695; 5,624,711; 5,658,734; and 5,700,637; the disclosures of which are herein incorporated by reference.  
         [0029]     Microarray technology allows for the measurement of the steady-state mRNA level of thousands of genes simultaneously thereby presenting a powerful tool for identifying the effect of FTIs on cell biology and the likely effect of treatment based on analysis of such effects. Two microarray technologies are currently in wide use. The first are cDNA arrays and the second are oligonucleotide arrays. Although differences exist in the construction of these chips, essentially all downstream data analysis and output are the same. The product of these analyses are typically measurements of the intensity of the signal received from a labeled probe used to detect a cDNA sequence from the sample that hybridizes to a nucleic acid sequence at a known location on the microarray. Typically, the intensity of the signal is proportional to the quantity of cDNA, and thus mRNA, expressed in the sample cells. A large number of such techniques are available and useful. Preferred methods for determining gene expression can be found in U.S. Pat. No. 6,271,002 to Linsley, et al.; U.S. Pat. No. 6,218,122 to Friend, et al.; U.S. Pat. No. 6,218,114 to Peck, et al.; and U.S. Pat. No. 6,004,755 to Wang, et al., the disclosure of each of which is incorporated herein by reference.  
         [0030]     Analysis of the expression levels is conducted by comparing such intensities. This is best done by generating a ratio matrix of the expression intensities of genes in a test sample versus those in a control sample. For instance, the gene expression intensities from a tissue that has been treated with a drug can be compared with the expression intensities generated from the same tissue that has not been treated with the drug. A ratio of these expression intensities indicates the fold-change in gene expression between the test and control samples.  
         [0031]     Gene expression profiles can also be displayed in a number of ways. The most common method is to arrange a ratio matrix into a graphical dendogram where columns indicate test samples and rows indicate genes. The data is arranged so genes that have similar expression profiles are proximal to each other (e.g.,  FIG. 1 ). The expression ratio for each gene is visualized as a color. For example, a ratio less than one (indicating down-regulation) may appear in the blue portion of the spectrum while a ratio greater than one (indicating up-regulation) may appear as a color in the red portion of the specrtum. Commercially available computer software programs are available to display such data including “OMNIVIZ PRO” software from Batelle and “TREE VIEW” software from Stanford  
         [0032]     The genes that are differentially expressed are either up regulated or down regulated in diseased cells following treatment with an FTI. Up regulation and down regulation are relative terms meaning that a detectable difference (beyond the contribution of noise in the system used to measure it) is found in the amount of expression of the genes relative to some baseline. In this case, the baseline is the measured gene expression of the untreated diseased cell. The genes of interest in the treated diseased cells are then either up regulated or down regulated relative to the baseline level using the same measurement method. Preferably, levels of up and down regulation are distinguished based on fold changes of the intensity measurements of hybridized microarray probes. A 1.5 fold difference is preferred for making such distinctions. That is, before a gene is said to be differentially expressed in treated versus untreated diseased cells, the treated cell is found to yield at least 1.5 times more, or 1.5 times less intensity than the untreated cells. A 1.7 fold difference is more preferred and a 2 or more fold difference in gene expression measurement is most preferred. Table 3 lists genes that were commonly modulated across all cell lines and in responder samples.  
         [0033]     A portfolio of genes is a set of genes grouped so that information obtained about them provides the basis for making a clinically relevant judgment such as a diagnosis, prognosis, or treatment choice. In this case, the judgments supported by the portfolios involve the treatment of leukemias with FTI&#39;s. Portfolios of gene expression profiles can be comprised of combinations of genes shown in Tables 1-3.  
         [0034]     One method of the invention involves comparing gene expression profiles for various genes to determine whether a person is likely to respond to the use of a therapeutic agent. Having established the gene expression profiles that distinguish responder from nonresponder, the gene expression profiles of each are fixed in a medium such as a computer readable medium as described below. A patient sample is obtained that contains diseased cells (such as hematopoietic blast cells in the case of AML) is then obtained. Sample RNA is then obtained and amplified from the diseased patient cell and a gene expression profile is obtained, preferably via micro-array, for genes in the appropriate portfolios. The expression profiles of the samples are then compared to those previously determined as responder and non-responder. If the sample expression patterns are consistent with an FTI responder expression pattern then treatment with an FTI could be indicated (in the absence of countervailing medical considerations). If the sample expression patterns are consistent with an FTI non-responder expression pattern then treatment with an FTI would not be indicated. Preferably, consistency of expression patterns is determined based on intensity measurements of micro-array reading as described above.  
         [0035]     In similar fashion, gene expression profile analysis can be conducted to monitor treatment response. In one aspect of this method, gene expression analysis as described above is conducted on a patient treated with an FTI at various periods throughout the course of treatment. If the gene expression patterns are consistent with a responder then the patient&#39;s therapy is continued. If it is not, then the patient&#39;s therapy is altered as with additional therapeutics such as tyrosine kinase inhibitor, changes to the dosage, or elimination of FTI treatment. Such analysis permits intervention and therapy adjustment prior to detectable clinical indicia or in the face of otherwise ambiguous clinical indicia.  
         [0036]     It is possible to attain ambiguous results in which some gene expression profiles are recorded that are in some respects indicative of a responder and in other respects indicative of a non-responder. For example, the profiles may show that three genes are up-regulated consistent with a responder but that another gene is not up-regulated as would ordinarily be the case for a responder. In such a case, statistical algorithms can be applied to determine the probability that the patient will respond or not respond to the drug. Statistical algorithms suitable for this purpose are well known and are available.  
         [0037]     Articles of this invention are representations of the gene expression profiles useful for treating, diagnosing, prognosticating, staging, and otherwise assessing diseases that are reduced to a medium that can be automatically read such as computer readable media (magnetic, optical, and the like). The articles can also include instructions for assessing the gene expression profiles in such media. For example, the articles may comprise a CD ROM having computer instructions for comparing gene expression profiles of the portfolios of genes described above. The articles may also have gene expression profiles digitally recorded therein so that they may be compared with gene expression data from patient samples. Alternatively, the profiles can be recorded in different representational format. A graphical recordation is one such format.  FIG. 1  shows an example of the graphical display of such a recordation. Clustering algorithms such as those incorporated in “OMNIVIZ” and “TREE VIEW” computer programs mentioned above can best assist in the visualization of such data.  
         [0038]     Additional articles according to the invention are nucleic acid arrays (e.g. cDNA or oligonucleotide arrays), as described above, configured to discern the gene expression profiles of the invention.  
         [0039]     Using clustering analysis (including the algorithms mentioned above) one can compare the expression levels of patient samples to establish regulatory relationships among genes with a certain statistical confidence. A dynamic map was constructed based upon such expression data. Such a genetic network map is useful for drug discovery. For example, once basic genes of interest were identified, a list of potential up-stream regulatory genes was found using such a genetic network map. The genes so identified or their expression products were then analyzed for their use as drug targets. In some embodiments, the regulatory function of the particular genes identified was used to identify therapeutics for use in treating leukemia.  
         [0040]     The regulation of transcription, RNA processing and RNA editing are all accomplished by proteins which are coded by their own genes. In addition, DNA sequences can exert long range control over the expression of other genes by positional effects. Therefore, the expression of genes is often regulated by the expression of other genes. Those regulatory genes are called upstream genes, relative to the regulated or down-stream genes. In a simple regulatory pathway: 
 
 A++&gt;B−−&gt;C++&gt;D  
 
 where: A, B, C, D are genes 
    ++ up-regulates     −− down-regulates 
 
 Gene A is an up-stream gene of gene B and B is an up-stream gene of C. One of skill in the art would appreciate that the network is frequently looped and inter-connected. In some instances, the expression of a gene is regulated by its own product as either a positive or negative feedback. 
   
 
         [0043]     Cluster analysis methods were used to group genes whose expression level is correlated. Methods for cluster analysis are described in detail in Harfigan (1975) Clustering Algorithms, NY, John Wile and Sons, Inc, and Everritt, (1980) Cluster Analysis 2nd. Ed. London Heineman Educational books, Ltd., incorporated herein for all purposed by reference. Path analysis was used to decompose relations among variables and for testing causal models for the genetic networks. Multiple primary targets of a drug in leukemic cells were identified as were drugs/drug classes useful in treating such cells. According to the current invention, drugs are any compounds of any degree of complexity that perturb a biological system.  
         [0044]     The biological effect of a drug may be a consequence of drug-mediated changes in the rate of transcription or degradation of one or more species of RNA, the rate or extent of translation or post-translational processing of one or more polypeptides, the rate or extent of the degradation of one or more proteins, the inhibition or stimulation of the action or activity of one or more proteins, and so forth. In addition to the FTI&#39;s that are preferred, the preferred drugs of this invention are those that modulate the MAPK/ERK signaling pathways, TGFβ, WNT or apoptotic pathways. These include, without limitation, tyrosine kinase inhibitors, MEK kinase inhibitors, P13K kinase inhibitors, MAP kinase inhibitors, apoptosis modulators and combinations thereof. Exemplary drugs that are most preferred among these are the “GLEEVEC” tyrosine kinase inhibitor of Novartis, U-0126 MAP kinase inhibitor, PD-098059 MAP kinase inhibitor, SB-203580 MAP kinase inhibitor, and antisense, ribozyme, and DNAzyme Bcl-XL anti-apoptotics. Examples of other useful drugs include, without limitation, the calanolides of U.S. Pat. No. 6,306,897; the substituted bicyclics of U.S. Pat. No. 6,284,764; the indolines of U.S. Pat. No. 6,133,305; and the antisense oligonucleotides of U.S. Pat. No. 6,271,210.  
         [0045]     As noted, the drugs of the instant invention can be therapeutics directed to gene therapy or antisense therapy. Oligonucleotides with sequences complementary to a mRNA sequence can be introduced into cells to block the translation of the mRNA, thus blocking the function of the gene encoding the mRNA. The use of oligonucleotides to block gene expression is described, for example, in, Strachan and Read, Human Molecular Genetics, 1996, incorporated herein by reference.  
         [0046]     These antisense molecules may be DNA, stable derivatives of DNA such as phosphorothioates or methylphosphonates, RNA, stable derivatives of RNA such as 2′-O-alkylRNA, or other antisense oligonucleotide mimetics. Antisense molecules may be introduced into cells by microinjection, liposome encapsulation or by expression from vectors harboring the antisense sequence.  
         [0047]     In the case of gene therapy, the gene of interest can be ligated into viral vectors that mediate transfer of the therapeutic DNA by infection of recipient host cells. Suitable viral vectors include retrovirus, adenovirus, adeno-associated virus, herpes virus, vaccinia virus, polio virus and the like. Alternatively, therapeutic DNA can be transferred into cells for gene therapy by non-viral techniques including receptor-mediated targeted DNA transfer using ligand-DNA conjugates or adenovirus-ligand-DNA conjugates, lipofection membrane fusion or direct microinjection. These procedures and variations thereof are suitable for ex vivo as well as in vivo gene therapy. Protocols for molecular methodology of gene therapy suitable for use with the gene is described in Gene Therapy Protocols, edited by Paul D. Robbins, Human press, Totawa N.J., 1996.  
         [0048]     Pharmaceutically useful compositions comprising the drugs of this invention may be formulated according to known methods such as by the admixture of a pharmaceutically acceptable carrier. Examples of such carriers and methods of formulation may be found in Remington&#39;s Pharmaceutical Sciences. To form a pharmaceutically acceptable composition suitable for effective administration, such compositions will contain an effective amount of the drug. The effective amount of the drug may vary according to a variety of factors such as the individual&#39;s condition, weight, sex and age. Other factors include the mode of administration. The pharmaceutical compositions may be provided to the individual by a variety of routes such as subcutaneous, topical, oral and intramuscular.  
         [0049]     The drugs of this invention include chemical derivatives of the base molecules of the drug. That is, they may contain additional chemical moieties that are not normally a part of the base molecule. Such moieties may improve the solubility, half-life, absorption, etc. of the base molecule. Alternatively the moieties may attenuate undesirable side effects of the base molecule or decrease the toxicity of the base molecule. Examples of such moieties are described in a variety of texts, such as Remington&#39;s Pharmaceutical Sciences.  
         [0050]     Compounds identified according to the methods disclosed herein may be used alone at appropriate dosages defined by routine testing in order to obtain optimal inhibition or activity while minimizing any potential toxicity. In addition, co-administration or sequential administration of other agents may be desirable.  
         [0051]     The drugs of this invention can be administered in a wide variety of therapeutic dosage forms in conventional vehicles for administration. For example, the drugs can be administered in such oral dosage forms as tablets, capsules (each including timed release and sustained release formulations), pills, powders, granules, elixirs, tinctures, solutions, suspensions, syrups and emulsions, or by injection. Likewise, they may also be administered in intravenous (both bolus and infusion), intraperitoneal, subcutaneous, topical with or without occlusion, or intramuscular form, all using forms well known to those of ordinary skill in the pharmaceutical arts. An effective but non-toxic amount of the compound desired can be employed as a modulating agent.  
         [0052]     The daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per patient, per day. For oral administration, the compositions are preferably provided in the form of scored or unscored tablets containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, and 50.0 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.0001 mg/kg to about 100 mg/kg of body weight per day. The range is more particularly from about 0.001 mg/kg to 10 mg/kg of body weight per day. The dosages are adjusted when combined to achieve desired effects. On the other hand, dosages of these various agents may be independently optimized and combined to achieve a synergistic result wherein the pathology is reduced more than it would be if either agent were used alone.  
         [0053]     Advantageously, compounds or modulators used in the present invention may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, compounds or modulators for the present invention can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches well known to those of ordinary skill in that art. To be administered in the form of a transdermal delivery system, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.  
         [0054]     For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents can be administered concurrently, or they each can be administered at separately staggered times.  
         [0055]     The dosage regimen utilizing the compounds or modulators in the present invention is selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular drug employed. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition. Optimal precision in achieving concentrations of drug within the range that yields efficacy without toxicity requires a regimen based on the kinetics of the drug&#39;s availability to target sites. This involves a consideration of the distribution, equilibrium, and elimination of a drug.  
         [0056]     The drugs of this invention can form the active ingredient, and are typically administered in admixture with suitable pharmaceutical diluents, excipients or carriers (collectively referred to herein as “carrier” materials) suitably selected with respect to the intended form of administration, that is, oral tablets, capsules, elixirs, syrups and the like, and consistent with conventional pharmaceutical practices.  
         [0057]     For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include, without limitation, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.  
         [0058]     For liquid forms the active drug component can be combined in suitably flavored suspending or dispersing agents such as the synthetic and natural gums, for example, tragacanth, acacia, methyl-cellulose and the like. Other dispersing agents that may be employed include glycerin and the like. For parenteral administration, sterile suspensions and solutions are desired. Isotonic preparations, which generally contain suitable preservatives, are employed when intravenous administration is desired.  
         [0059]     The drugs in the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.  
         [0060]     Drugs in the present invention may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The drugs in the present invention may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinyl-pyrrolidone, pyran copolymer, polyhydroxypropylmethacryl-amidephenol, polyhydroxy-ethylaspartamidephenol, or polyethyl-eneoxidepolylysine substituted with palmitoyl residues. Furthermore, the drugs in the present invention may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydro-pyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.  
         [0061]     For oral administration, the drugs may be administered in capsule, tablet, or bolus form or alternatively they can be mixed with feed. The capsules, tablets, and boluses are comprised of the active ingredient in combination with an appropriate carrier vehicle such as starch, talc, magnesium stearate, or di-calcium phosphate. These unit dosage forms are prepared by intimately mixing the active ingredient with suitable finely-powdered inert ingredients including diluents, fillers, disintegrating agents, and/or binders such that a uniform mixture is obtained. An inert ingredient is one that will not react with the drugs and which is non-toxic to the animal being treated. Suitable inert ingredients include starch, lactose, talc, magnesium stearate, vegetable gums and oils, and the like. These formulations may contain a widely variable amount of the active and inactive ingredients depending on numerous factors such as the size and type of the animal species to be treated and the type and severity of the infection. The active ingredient may also be administered by simply mixing the compound with the feedstuff or by applying the compound to the surface of the foodstuff.  
         [0062]     The compounds or modulators may alternatively be administered parenterally via injection of a formulation consisting of the active ingredient dissolved in an inert liquid carrier. Injection may be either intramuscular, intraruminal, intratracheal, or subcutaneous. The injectable formulation consists of the active ingredient mixed with an appropriate inert liquid carrier. Acceptable liquid carriers include the vegetable oils such as peanut oil, cotton seed oil, sesame oil and the like as well as organic solvents such as solketal, glycerol formal and the like. As an alternative, aqueous parenteral formulations may also be used. The vegetable oils are the preferred liquid carriers. The formulations are prepared by dissolving or suspending the active ingredient in the liquid carrier such that the final formulation contains from 0.005 to 10% by weight of the active ingredient.  
         [0063]     The invention is further illustrated by the following nonlimiting examples.  
       EXAMPLE 1  
     Cell Culture  
       [0064]     The AML-like cell lines HL-60 (promyelocytic) and U-937 (promonocytic) were obtained from the ATCC. AML-193 (monocytic) and THP-1 (monocytic) cells were obtained from the RW Johnson Pharmaceutical Research Center, San Diego. Cells were grown in Roswell Park Memorial Institute medium (RPMI) with 20% Fetal Bovine Serum (FBS). AML-193 was also supplemented with granulocyte-macrophage colony-stimulating factor (GM-CSF) (10 ng/ml), insulin (0.005 mg/ml), and transferrin (0.005 mg/ml).  
       EXAMPLE 2  
     Toxic Dose Assay  
       [0065]     The cells of Example 1 were inoculated into 6-well plates at an initial concentration of 1×10 5  cells/ml. (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone) was added at concentrations ranging form  0.5 to 500 nM in 3 μl of DMSO directly to the culture medium. Control cells from Example 1 were grown in medium alone or in medium supplemented with vehicle (0.1% DMSO). Cell numbers were counted at days four and seven in a hemocytometer and cell viability was determined by trypan blue exclusion assay. The IC 50  was defined as the dose at which the number of viable cells in the treated sample was 50% of that in the control at day seven. Calculations were made based on duplicate runs of the experiment. The IC 50  of the four cell lines was calculated after seven days of treatment with the FTI. AML-193 had an IC 50  of 134 nM, HL-60 had an IC 50  of 24 nM, THP-1 had an IC 50  of 19 nM, and U-937 had an IC 50  of 44 nM. This indicated that the four AML-like cell lines were sensitive to FTI treatement.  
       EXAMPLE 3  
     Time Course Assay  
       [0066]     Duplicate cultures of the cells of Example 1 were inoculated into 6-well plates at an initial concentration of 1×10 5  cells/ml. (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone) was supplemented at a concentration of  100 nM in 3 μl of DMSO directly to the culture medium. The concentration of 100 nM was chosen for the subsequent time course experiments to normalize the treatment protocol based, in part, on the results of Example 2. Duplicate control cultures were grown in medium containing 0.1% DMSO. Duplicate cultures were harvested daily for a total of six days. Cells were counted, assayed for viability, and total RNA isolated according to the manufacturer&#39;s protocol (Qiagen RNeasy). The analysis showed that cells from different cell lines were effected at different times. RNA was treated with DNase1 (Qiagen DNase1 kit) to remove any residual genomic DNA. Linear amplification of RNA was conducted according to the procedure described in U.S. Pat. No. 5,545,522 to Van Gelder et. al. Aliquots of 5 μg of aRNA were then prepared for hybridization to cDNA arrays.  
       EXAMPLE 4  
     Bone Marrow Processing  
       [0067]     Bone marrow aspirates were obtained from two patients diagnosed with AML who had been treated with FTI. These AML patients were administered 600 mg (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone) twice daily over a  21 day period. Bone marrow aspirates were taken at baseline and once a week for the three weeks of treatment. One of these patients did not respond (RH) while the other responded (BS) to the FTI. Response was determined as a reduction of more than 50% of blast cells in bone marrow aspirates. The aspirates were diluted to 15 ml with PBS and Ficoll-density centrifuged. White blood cells were washed twice with PBS, resuspended in FBS with 10% DMSO and immediately frozen at −80° C. Cells were cryogenically preserved to maintain cell viability. Samples were thawed at 37° C. and 10× volume of RPMI with 20% FBS was added drop-wise over a period of 5 min. Cells were centrifuged at 1600 rpm for 10 min and resuspended in 10 ml PBS with 2 mM EDTA and 0.5% BSA. Samples were then passed through a 70 μM filter to remove any cell clumps. Cell viability was determined by Trypan Blue assay. If sample viability was less than 50% a Miltenyi Dead Cell Removal Kit was employed to enrich for the live cell fraction. 2×10 5  viable cells were then double labeled with CD33-FITC and CD34-PE antibodies (Pharminigen) and FACS analysis was performed. Post (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone)-treated bone marrow samples were enriched for leukemic cells by magnetic bead cell separation using either CD 33 or CD34 antibodies (Miltenyi). The extracted cells had RNA extracted as described in Example 3.  
       EXAMPLE 5  
     Probe Preparation  
       [0068]     RNA samples obtained in Examples 3 and 4 were prepared for hybridization to cDNA microarrays according to the following procedure. One to two rounds of linear amplification was performed on total RNA depending on the amount of starting material. Initially, 1-10 μg total RNA was reverse transcribed using the Superscript cDNA transcription kit (Gibco BRL). Ten μl total RNA was first mixed with 1 μl of 0.5 mg/ml T7-oligodT primer, incubated at 70° C. for 10 min, and then chilled on ice. Next, 8 μl of 5× first-strand reaction buffer, 0.1M DTT, 10 mM dNTPs, and 1 μl Rnase Block were added, and the solution incubated at 42° C. for 5 min. One μl Superscript II was then added and the reaction was incubated at 42° C. for 2 hr. The reaction was heat deactivted at 70° C. for 10 min and 1 μl was removed for PCR. Next, 92 μl Rnase-free water, 30 μl 5× second-strand reaction buffer, 3 μl 10 mM dNTP, 4 μl DNA polymerase 1, 1 μl  E. coli  Rnase H, 1 μl  E. coli  DNA ligase were added and the mixture incubated at 16° C. for 2 hr. cDNA was linear amplified using the Ampliscribe T7-transcription kit (Epicenter). If required, a second round of RNA amplification was performed by the random hexamer approach. Fluorescently labeled cDNA probes were synthesized by priming aRNA with random hexamers and including Cy3-dCTP in the nucleotide mix. Reactions were purified using a QIAquick PCR purification kit (Qiagen), the volumes of probe normalized using relative fluoresence (Cytofluor), and resuspended in 50 μl of Version 2 hybridization buffer (Amersham Pharmacia Biotech, Pistcataway, N.J.) with 50% formamide and human Cot1 DNA (Life Technologies).  
       EXAMPLE 6  
     Array Hybridization and Analysis  
       [0069]     The arrays contained 7452 cDNAs from the IMAGE consortium (Integrated Molecular Analysis of Genome and their Expression: Research Genetics, Huntsville, Ala.) and Incyte libraries. Micro-arrays were generated as follows and probes hybridized as described in Example 5. cDNAs were printed on amino silane-coated slides (Corning) with a Generation III Micro-array Spotter (Molecular Dynamics). The cDNAs were PCR amplified, purified (Qiagen PCR purification kit), and mixed 1:1 with 10 M NaSCN printing buffer. Prior to hybridization micro-arrays were incubated in isopropanol at room temperature for 10 min. The probes were incubated at 95° C. for 2 min, at room temperature for 5 min, and then applied to three replicate slides. Cover slips were sealed onto the slides with DPX (Fluka) and incubated at 42° C. overnight. Slides were then washed at 55° C. for 5 min in 1×SSC/0.2% SDS and 0.1×SSC/0.2% SDS, dipped in 0.1×SSC and dried before being scanned by a GenIII Array Scanner (Molecular Dynamics). The fluorescence intensity for each spot was analyzed with AUTOGENE software (Biodiscovery, Los Angeles).  
         [0070]     The intensity level of each micro-array was normalized so that the 75 th  percentile of the expression levels was equal across micro-arrays. Clones displaying a coefficient of variance (CV) greater than 50% of the mean were excluded from the analysis. Since background intensity was a maximum of 32 units for all experiments a threshold of 32 was assigned to all clones exhibiting an expression level lower than this. A ratio matrix was then generated based on pair-wise analysis of treated and control samples and Hierarchical clustering was performed using an euclidean metric and average linkage (Omniviz Pro™).  
         [0071]     Each sample was hybridized to three identical arrays and the mean signal intensity was compared by scatter-plot analysis. High correlation coefficients were also observed when control samples were compared to treated samples from the same day. This indicated there were no gross changes in gene expression due to treatment with (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone). In addition, the variation between control samples from different days was examined. Cells were mock-treated and RNA was isolated after  1, 2, 3, 4, 5, and 6 days. Following labeling and hybridization the mean intensity of duplicate samples and the coefficient of variance (CV) of each clone (3 spots per clone) were calculated. Data points which displayed a CV of more than 50% were discarded from further analysis.  
         [0072]     Genes analyzed according to this invention are identified by reference to Gene ID Numbers in the Genbank database. Where no such ID Numbers are available, nucleic acid sequences corresponding to the modulated genes are provided. These are typically related to full length nucleic acid sequences that code for the production of a protein or peptide. One skilled in the art will recognize that identification of full-length sequences is not necessary from an analytical point of view. That is, portions of the sequences or ESTs can be selected according to well-known principles for which probes can be designed to assess gene expression for the corresponding gene.  
       EXAMPLE 7  
     Differential Gene Expression in Treated Cell Line Samples  
       [0073]     Hierarchical clustering was performed on the time-course data sets using the OmniViz Pro™ software (Battelle). Initially, fold-changes of 1.5, 1.7, and 2.0 were used as filters for the treated versus control intensity ratios for each day of the time-course. The gene expression profiles of genes modulated beyond these thresholds were analyzed to examine those genes that were commonly modulated between the three data sets and identify gene clusters that shared similar expression profiles. Results are shown in Tables 1-3 below.  
       EXAMPLE 8  
     Identification of Gene Networks  
       [0074]     Genes that were regulated in two or more cell lines by at least 1.5-fold in drug treated cell lines (Table 1) were identified as described above. The list of these genes was employed to identify major gene pathways that were being modulated by the most preferred FTI, (B)-6-[amino(4-chlorophenyl)(1-methyl-   1H -imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-   2(1H )-quinolinone). If clones did not perfectly match a known gene annotations from the best BLAST result of the clone sequence were used. Since the level of regulation of these genes varied over the course of treatment of the cell lines, the gene expression profiles from the primary AML tissue that responded to this FTI were determined.    
         [0075]     It was found that many genes in the MAPK/ERK ( FIG. 2 ) signaling pathways were being down-regulated and that genes in the TGFβ ( FIG. 3 ) and WNT ( FIG. 3 ) signaling pathways were generally up-regulated, while apoptotic pathways were also activated ( FIG. 4 ). This allowed the identification of other gene targets sensitive to treatment with known or novel drug compounds. For example, beneficial treatment can result from FTIs used in conjunction with tyrosine kinase, MEK kinase, PI3K and/or MAP kinase inhibitors to obtain a more potent effect. In addition, given the finding that apoptotic pathways are activated in FTI treated cells, drugs that modulate apoptosis could be expected to have beneficial effect when employed in conjunction with an FTI. Examples of these types of compounds include tyrosine kinase inhibitors (eg Gleevec, Novartis), MAP kinase inhibitors (eg U-0126, PD-098059, SB-203580), and inhibitors of anti-apoptotic genes such as Bcl-XL (eg antisense, ribozymes, DNAzymes).  
                                                   TABLE 1                           Genes (by Genbank Accession Number) modulated       at least 1.5 fold in 2 or more       of the cell lines over the 6 day time course.                Gene ID   Accession No.   Seq ID                            3434105F7   AB026898   846           3881595H1   AC000134   691           AI939481   AC005155   870           AA961061   AC005670   879           3918104H1   AC006023   706           AI025519   AC008427   529           5543360F8   AC009220   738           AA744682   AC009289   498           AA932129   AC009756   523           AI148008   AC011473   882           Y00052   AC013722   54           R52476   AC021078   639           AA864819   AC022087   875           AI815593   AC022150   581           AI141943   AC026448   520           AI300541   AC073585   536           2515486H1   AF161372   353           1731618H1   AJ003147   822           BE222911   AJ400879   885           R13802   AK022901   807           AI656222   AL021155   898           AI553823   AL022313   775           AA010251   AL034397   46           AA237071   AL035420   467           2445101F6   AL049824   328           AI638342   AL122004   575           AA779424   AL136980   492           H81171   AL137073   608           R77754   AL137790           AI209040   AL139082   543           6421806H1   AL139396   732           H61066   AL161787   605           R59209   AL355136   640           AA486141   AL355352   471           AI339252   AP001630   884           AW023438   BC009732   790           914979H1   BC013834   419           AA455969   D00015   20           T64335   D00017   450           X02308   D00596   254           X67098   D00596   278           X01023   D10493   252           D10493   D10493   400           Y00396   D10493   395           X69292   D10667   279           AA736561   D11094   753           S68252   D11139   449           M25315   D12592   90           AL186110   D13118   532           H84153   D13639   153           AA598561   D14043   6           D14695   D14695   136           2206642T6   D16889   351           AI878943   D17004   433           U38846   D17080   73           J03801   D21235   401           AI762926   D23660   565           D25215   D25215   138           U41078   D26512           AA485961   D30648   470           AA456408   D38441   21           AI311090   D38616   555           1869911H1   D42084   692           D43950   D43950   106           AW006368   D44467   585           U29092   D45050   235           D45887   D45887   437           W68193   D49489           3633286H1   D63874   415           N76967   D66904   201           AA985407   D82326   525           AI962797   D83260   593           M59829   D85730   82           3107995H1   D86322   359           AA279906   D86550   481           AI016874   D86586   528           556963H1   D86955   309           AI810687   D86997   788           AF045581   D87462   129           U41070   D89078   75           D90209   D90209   141           AA812265   D90767   501           2135769H1   J02763   350           1876511H1   J03072   643           J04088   J04088   156           AI590075   J04973   778           H30357   J05451   800           K00558   K03460   158           L10413   L00634   164           L01087   L01087   122           AI027898   L02426   516           L06139   L06139           U28936   L07914   71           M86400   L07955   76           AA428915   L08634   424           AA464627   L09604   18           M94859   L10284   222           R78541   L10717           L15189   L11066           L11284   L11284           T87908   L12387   452           T80827   L13802   451           L08044   L15203   163           AI278029   L16862   766           M60278   L17032   301           M60278   L17032   301           M65128   L18980   84           W49672   L20861   249           L22005   L22005   167           AI380522   L23822   552           AA988469   L25591   526           L26336   L26336   112           AI074564   L32866   539           M63175   L35233   194           2470939H1   L35848   830           AA190648   L36055   423           AI243166   L38716   892           L39833   L39833   893           M97347   L41415   444           2005142H1   L42324   348           M11723   L43615   101           U04045   L47574   231           AA284067   L76938   877           M13142   M13142   102           W68291   M15395   250           5560880H1   M19483   861           3171275H1   M20199   683           M22489   M22489   403           AA070627   M22810   421           H39560   M24736   146           M25897   M25897   91           M27492   M27492   181           AA570304   M29366           205581R6   M29696   349           M84739   M32294           M84739   M32294           M35857   M32315   189           3801801H1   M33680   366           M63904   M63904   83           AI091579   M63971   518           M69215   M69215   85           M74782   M74782   216           M80254   M80254   86           M80647   M80647   218           M84526   M84526   88           6805226H1   M84526   418           S93414   M86553   78           M91556   M91556   77           M95678   M95678   223           2017923F6   M96326   825           H73054   NM_000551   151           AA488324   NM_001211   388           N73242   NM_001274   199           AF013611   NM_001335           AW163686   NM_001524   589           AI921879   NM_002287   574           AI652785   NM_002333   554           AI423526   NM_003332   559           3028719F6   NM_003600   680           AB010882   NM_003601   123           AF030424   NM_003642   126           AW194791   NM_003668   613           AF075599   NM_003969   132           AF031141   NM_004223   127           2676931T6   NM_004412   312           AF053304   NM_004725   130           AF119815   NM_004885   399           AI816398   NM_004888   571           2185556H1   NM_004917   326           3357511H1   NM_004917           AA047585   NM_005109   477           AA448972   NM_005592   503           AW629084   NM_005817   615           AJ001015   NM_005854   104           AJ001016   NM_005856   105           U85055   NM_006480   407           3618886F6   NM_006536   319           AA906714   NM_006573   759           AF060153   NM_007037   398           1467864F6   NM_012089           AI097079   NM_012100   763           AF204944   NM_012105   527           W44673   NM_012428   670           AI522316   NM_013386   774           AI700673   NM_013439   577           AA057781   NM_014172   40           AI299795   NM_014251   547           1931159F6   NM_014397   346           AW630208   NM_014413   795           2821685T6   NM_014967   357           1539060H1   NM_015343   334           AI762738   NM_015449   579           AA401397   NM_015596   384           AW243944   NM_015596   791           AI436551   NM_016141   553           AI651159   NM_016440   576           AA527334   NM_016625   508           g922698   NM_017555   380           1693028H1   NM_017636   345           002783H1   NM_017860   339           AI368583   NM_017874   429           AW170305   NM_017903   612           H62827   NM_018321   634           M78706   NM_019020   217           BE048230   NM_020216           AI214466   NM_020334   535           AA452802   NM_021196   389           AI808824   NM_022082   787           W77977   NM_022336   815           AA535015   NM_022570   475           AA861140   NM_022829   521           AW078834   NM_023080   587           5122087H1   NM_024056   369           AF017182   NM_024101   393           AA449040   NM_024116   483           2792728F6   NM_024902   356           BE218593   NM_025230   630           AA669885   NM_030763   750           AI339565   NM_030908   767           AF038564   NM_031483   128           AI126706   NM_032038   519           1961084H1   NM_032188   824           4609810F6   NM_032554   713           AA745592   NM_032844   490           AW612141   NM_033050   793           AI740538   NM_033280   785           U58522   S51016   242           M57703   S63697   190           AA873257   S73591   758           AA521213   S77359   473           N77754   S79873   202           AA984230   S80071   524           R79935   S81439   213           T71391   T71391   665           AA598776   U05340   8           U11053   U11053   80           T55353   U12597   227           AA456616   U14970   22           U18300   U18300   234           AF017306   U20657   124           AA459663   U25182   19           U27699   U27699   880           AI884916   U29171   591           U29171   U29171   454           1671033F6   U33429   337           AA017042   U40989   44           AI126520   U48405   542           U48807   U48807           U49395   U49395   239           AA186542   U50078   464           U51586   U51586   240           AW150605   U54558   434           AA455800   U55206   25           AF029777   U57316   426           I19355   U58913   118           319095H1   U58913   307           AF027964   U59911   125           U60519   U60519   62           AI371158   U65378   557           U69883   U69883   244           H30148   U73641   601           R80718   U75283   620           U77180   U77180   246           U78180   U78180   64           U83115   U83115   889           AA938905   U86218   514           AI401546   U88844   770           2526581H1   U90904   650           AA773114   U95740   499           AA176596   U96781   478           X13274   V00543   258           I16618   V00595   155           R91899   X00226   660           AW519155   X00318   436           X87344   X00369   894           X02910   X01394           M15840   X02532   172           AA401046   X02592   482           X02812   X02812           X87344   X03066   894           X03084   X03084           M10901   X03225   99           X03225   X03225   99 (?)           R81823   X03742   447           X04011   X04011           K02400   X04076   159           X07036   X04408   56           X07036   X04408   56           Y00816   X05309   293           N20475   X05344   225           M11233   X05344   100           X02544   X05784           X52192   X06292           R33755   X06547   207           X06989   X06989   256           X07979   X07979   257           X14723   X08004   259           M20566   X12830   178           M20566   X12830   178           X13197   X13197   408           M21304   X13709   179           X00351   X13839   251           X60236   X14008   410           H57180   X14034   148           M33011   X14758   441           X14768   X14768   58           M31625   X14768   96           M31626   X14768   97           M30816   X14768   95           X52882   X14983   59           AA598758   X15187   7           X15606   X15606   261           K03515   X16539   161           AA868186   X17093   425           X51416   X51416           M23699   X51439   180           AA455222   X51675   24           X51757   X51757           X52195   X52195   263           U06434   X53682   232           J03198   X54048   119           M32304   X54533   187           AA487812   X56134   9           X56134   X56134   265           M16985   X56257   174           N31660   X56257           H27379   X57198   144           X57522   X57522   268           X57830   X57830   60           M57765   X58377   191           X58528   X58528   269           M81182   X58528   219           S60489   X60111   305           AI739095   X61157   563           R76314   X61587   212           M83665   X62534   404           X65921   X65921   277           M37722   X66945   98           AA453816   X69516   26           AA187162   X69654   422           X69819   X69711   280           X70070   X70070   61           X70697   X70697   281           S40706   X71427   303           T53775   X71874   226           X71877   X71877   47           X73458   X73458   283           X74801   X74801           AA454585   X75755   2           R43734   X76939           AI189206   X77303   533           2496221H1   X77303   831           H17504   X80692           R26434   X80910   205           X83688   X83688   285           U24231   X84709   302           3576337H1   X85030   318           X87212   X87212   50           T56477   X87212   622           AA464034   X89401   16           X89576   X89576   51           AA187458   X92396   35           M15887   X94565   173           X94991   X94991   457           X96427   X96427   287           X97058   X97058           AA425120   X98262   28           3283686H1   XM_005825   684           AW027188   XM_005958   597           1525902F6   XM_006646           R48796   XM_008099   210           AK000599   XM_027140   584           AA044653   XM_031608   476           AW665954   XM_035574   617           H86407   XM_037453   802           R00285   XM_038150   609           X57447   XM_039395   267           778372H1   XM_040459   375           R82530   XM_041024   448           AI580830   XM_042041   562           3097063H1   XM_044784           3038910H1   XM_046691   358           H53340   XM_048213   147           1654210F6   XM_048530   336           L42856   XM_054964   168           2707270F6   XM_056259   355           M23468   Y00062           Y00649   Y00649   291           Y00757   Y00757   292           M17017   Y00787   175           M28130   Y00787   92           L02932   Y07619   108           Y10256   Y10256   294           AA454813   Y12395   1           AA149850   Y12670   466           704183H1   Y13710           059476H1   Y13829   340           Y13834   Y13834   458           L11016   Y14768   165           3141315H1   Y17803   361           AI341167   Y18391   768           AI707852   Z12962   432           U51278   Z23115   394           AI686653   Z26876   430           AA043102   Z35102   459           AA136533   Z35481   381           U49083   Z49148   455           R70234   Z56852   446           257274R6   Z58168   354           U62027   Z73157   63           391237F1   Z73157   367           510997F1   Z73157   368           AI808621   Z82214   569           AA460801   Z98749           2673259F6   Z98752   699           R22977   Z98946   204           L03380   Z99995   402           AA425422       29           AA460392       504           AA508510       472           AA552028       509           AA576785       510           AA663307       748           AI015248       872           AI024468       896           AI086865       540           AI190605       897           AI203269       871           AI264420       545           AI333013       556           AI435052       771           AI671268       781           AI796718       568           AI990816       594           AW027164       596           AW167520       891           H24679       633           H66015       636           H91370       637           W07570       667           1274737F6       672           195337H1       347           2398102H1       647           2531082H1       698           264639H1       329           2794246F6       654           3290073H1       685           335737H1       362           4539942F8       711           6300669H1       417           938765H1                      
 
         [0076]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                   
               
               
                 Genes (by GenBank Accession Number) 
               
               
                 modulated at least 1.7 fold in primary AML Sample. 
               
             
          
           
               
                   
                 Gene ID 
                 Accession No. 
                 Seq ID 
               
               
                   
                   
               
             
          
           
               
                   
                 T94331 
                 AB026898 
                 810 
               
               
                   
                 3881595H1 
                 AC000134 
                 691 
               
               
                   
                 1329021F6 
                 AC002073 
                 816 
               
               
                   
                 2858615H1 
                 AC002325 
                 836 
               
               
                   
                 AI791539 
                 AC002428 
                 566 
               
               
                   
                 AI821217 
                 AC004258 
                 582 
               
               
                   
                 AA774798 
                 AC004671 
                 868 
               
               
                   
                 H29666 
                 AC004845 
                 600 
               
               
                   
                 T95173 
                 AC005071 
                 811 
               
               
                   
                 AA814523 
                 AC005160 
                 887 
               
               
                   
                 5905620T9 
                 AC005212 
                 731 
               
               
                   
                 5986963H1 
                 AC005280 
                 865 
               
               
                   
                 5825251H1 
                 AC005306 
                 864 
               
               
                   
                 N36113 
                 AC005670 
                 886 
               
               
                   
                 1700438H1 
                 AC005682 
                 412 
               
               
                   
                 R48756 
                 AC005757 
                 638 
               
               
                   
                 5538589F6 
                 AC005839 
                 859 
               
               
                   
                 3918104H1 
                 AC006023 
                 706 
               
               
                   
                 AA443719 
                 AC007240 
                 468 
               
               
                   
                 AI867297 
                 AC007883 
                 590 
               
               
                   
                 R63067 
                 AC008073 
                 659 
               
               
                   
                 AW022174 
                 AC008382 
                 595 
               
               
                   
                 5537789F6 
                 AC008525 
                 721 
               
               
                   
                 H00249 
                 AC008733 
                 599 
               
               
                   
                 1436240H1 
                 AC008860 
                 674 
               
               
                   
                 2668191F6 
                 AC008949 
                 833 
               
               
                   
                 5543360F8 
                 AC009220 
                 738 
               
               
                   
                 AA737674 
                 AC009892 
                 881 
               
               
                   
                 5104579H1 
                 AC009892 
                 718 
               
               
                   
                 3335217F6 
                 AC010311 
                 686 
               
               
                   
                 BE326380 
                 AC010521 
                 631 
               
               
                   
                 3746214H1 
                 AC011088 
                 689 
               
               
                   
                 1671315F6 
                 AC011500 
                 820 
               
               
                   
                 H60969 
                 AC012351 
                 604 
               
               
                   
                 AA926944 
                 AC012377 
                 512 
               
               
                   
                 3100089H1 
                 AC012454 
                 682 
               
               
                   
                 Y00052 
                 AC013722 
                 54 
               
               
                   
                 R52476 
                 AC021078 
                 639 
               
               
                   
                 N45149 
                 AC021106 
                 803 
               
               
                   
                 AI742120 
                 AC022137 
                 564 
               
               
                   
                 4177228F6 
                 AC022224 
                 855 
               
               
                   
                 2676312H1 
                 AC022415 
                 652 
               
               
                   
                 H73476 
                 AC022740 
                 607 
               
               
                   
                 AA652121 
                 AC046170 
                 487 
               
               
                   
                 AI308320 
                 AC046170 
                 890 
               
               
                   
                 1956982H1 
                 AC046170 
                 645 
               
               
                   
                 1428534F6 
                 AC051619 
                 818 
               
               
                   
                 2914934H1 
                 AC055707 
                 701 
               
               
                   
                 AA621370 
                 AC064807 
                 511 
               
               
                   
                 5514511R6 
                 AC073333 
               
               
                   
                 AI698737 
                 AC074331 
                 783 
               
               
                   
                 3406131H1 
                 AC079118 
                 724 
               
               
                   
                 N20072 
                 AC096579 
                 224 
               
               
                   
                 5911413H1 
                 AC096667 
               
               
                   
                 AI458182 
                 AF042782 
                 773 
               
               
                   
                 2291436H1 
                 AF074333 
                 646 
               
               
                   
                 W32067 
                 AF136745 
                 669 
               
               
                   
                 6755801J1 
                 AF157623 
                 746 
               
               
                   
                 2397317F6 
                 AF235100 
                 827 
               
               
                   
                 R53190 
                 AF384819 
                 619 
               
               
                   
                 1731618H1 
                 AJ003147 
                 822 
               
               
                   
                 2959801H1 
                 AJ003147 
                 703 
               
               
                   
                 3123232H1 
                 AJ003147 
                 840 
               
               
                   
                 2760110H1 
                 AJ006345 
                 314 
               
               
                   
                 X64073 
                 AJ239325 
                 274 
               
               
                   
                 3986782F7 
                 AJ249275 
                 850 
               
               
                   
                 AI366098 
                 AJ276674 
                 769 
               
               
                   
                 AI695385 
                 AJ289236 
                 899 
               
               
                   
                 BE222911 
                 AJ400879 
                 885 
               
               
                   
                 AI400473 
                 AK017738 
                 558 
               
               
                   
                 AI299633 
                 AK021499 
                 546 
               
               
                   
                 R13802 
                 AK022901 
                 807 
               
               
                   
                 1489075H1 
                 AK025775 
                 343 
               
               
                   
                 AI656222 
                 AL021155 
                 898 
               
               
                   
                 W96144 
                 AL021155 
                 626 
               
               
                   
                 2459540H1 
                 AL031282 
                 829 
               
               
                   
                 3461693F6 
                 AL031588 
                 687 
               
               
                   
                 4333034H1 
                 AL031726 
                 709 
               
               
                   
                 3332309H1 
                 AL031728 
                 705 
               
               
                   
                 R61661 
                 AL032821 
                 658 
               
               
                   
                 U71321 
                 AL033519 
                 406 
               
               
                   
                 AA935151 
                 AL034374 
                 513 
               
               
                   
                 AA010251 
                 AL034397 
                 46 
               
               
                   
                 U43431 
                 AL035367 
                 238 
               
               
                   
                 AA237071 
                 AL035420 
                 467 
               
               
                   
                 AA609779 
                 AL049610 
                 114 
               
               
                   
                 AA167461 
                 AL049612 
                 463 
               
               
                   
                 4228729H2 
                 AL049742 
                 857 
               
               
                   
                 6712339H1 
                 AL049766 
                 867 
               
               
                   
                 AI051176 
                 AL049872 
                 531 
               
               
                   
                 1747028H1 
                 AL078600 
                 642 
               
               
                   
                 5164454H1 
                 AL109840 
                 370 
               
               
                   
                 7007735H1 
                 AL117382 
                 742 
               
               
                   
                 AA526337 
                 AL121601 
                 495 
               
               
                   
                 AI638342 
                 AL122004 
                 575 
               
               
                   
                 4835576H1 
                 AL122035 
                 715 
               
               
                   
                 W01596 
                 AL133243 
                 812 
               
               
                   
                 U64205 
                 AL133367 
               
               
                   
                 4820983H1 
                 AL135786 
                 714 
               
               
                   
                 5594552H1 
                 AL136381 
                 723 
               
               
                   
                 H12102 
                 AL136979 
                 798 
               
               
                   
                 H81171 
                 AL137073 
                 608 
               
               
                   
                 AA151374 
                 AL137790 
                 37 
               
               
                   
                 AA578089 
                 AL138787 
                 496 
               
               
                   
                 AI209040 
                 AL139082 
                 543 
               
               
                   
                 6421806H1 
                 AL139396 
                 732 
               
               
                   
                 H60498 
                 AL157776 
                 603 
               
               
                   
                 3721604H1 
                 AL160271 
               
               
                   
                 H61066 
                 AL161787 
                 605 
               
               
                   
                 2798009H1 
                 AL162252 
                 834 
               
               
                   
                 2225447F6 
                 AL162430 
                 695 
               
               
                   
                 AI885557 
                 AL162729 
                 573 
               
               
                   
                 2918417F6 
                 AL163279 
                 657 
               
               
                   
                 AA489975 
                 AL355151 
                 505 
               
               
                   
                 U77456 
                 AL355794 
                 247 
               
               
                   
                 5375277T9 
                 AL356266 
                 735 
               
               
                   
                 AI051860 
                 AL356489 
                 517 
               
               
                   
                 4019605F6 
                 AL356489 
                 851 
               
               
                   
                 U29607 
                 AL356801 
                 236 
               
               
                   
                 AA861429 
                 AL359512 
                 757 
               
               
                   
                 AA767859 
                 AL359915 
                 756 
               
               
                   
                 1362587H1 
                 AL391122 
                 627 
               
               
                   
                 R09122 
                 AL391194 
                 806 
               
               
                   
                 R93094 
                 AP000173 
                 662 
               
               
                   
                 AA954331 
                 AP000432 
                 760 
               
               
                   
                 R10535 
                 AP000555 
                 611 
               
               
                   
                 5327443H1 
                 AP000936 
                 720 
               
               
                   
                 1569726H1 
                 AP001347 
                 676 
               
               
                   
                 R92422 
                 AP001672 
                 661 
               
               
                   
                 3422674H1 
                 AP002800 
                 364 
               
               
                   
                 AI310451 
                 AP002812 
                 550 
               
               
                   
                 3568042H1 
                 AP003900 
                 725 
               
               
                   
                 AA455969 
                 D00015 
                 20 
               
               
                   
                 AF030575 
                 D00015 
                 427 
               
               
                   
                 T64335 
                 D00017 
                 450 
               
               
                   
                 D12614 
                 D00102 
                 135 
               
               
                   
                 X67098 
                 D00596 
                 278 
               
               
                   
                 R27585 
                 D00759 
                 206 
               
               
                   
                 AA465593 
                 D00762 
                 15 
               
               
                   
                 M80436 
                 D10202 
                 87 
               
               
                   
                 M80436 
                 D10202 
                 87 
               
               
                   
                 M80436 
                 D10202 
                 87 
               
               
                   
                 M80436 
                 D10202 
                 87 
               
               
                   
                 AA464600 
                 D10493 
                 17 
               
               
                   
                 AI147046 
                 D10653 
                 764 
               
               
                   
                 S68252 
                 D11139 
                 449 
               
               
                   
                 M25315 
                 D12592 
                 90 
               
               
                   
                 AI186110 
                 D13118 
                 532 
               
               
                   
                 S57708 
                 D13515 
                 304 
               
               
                   
                 D13626 
                 D13626 
               
               
                   
                 AA682625 
                 D13641 
                 497 
               
               
                   
                 AA598561 
                 D14043 
                 6 
               
               
                   
                 D14695 
                 D14695 
                 136 
               
               
                   
                 D14825 
                 D14825 
                 137 
               
               
                   
                 855326R1 
                 D16234 
               
               
                   
                 L20046 
                 D16305 
                 166 
               
               
                   
                 V00496 
                 D17206 
                 456 
               
               
                   
                 AA629808 
                 D17554 
                 382 
               
               
                   
                 M57285 
                 D21214 
                 81 
               
               
                   
                 J03801 
                 D21235 
                 401 
               
               
                   
                 AI700360 
                 D21878 
                 431 
               
               
                   
                 D25216 
                 D25216 
                 139 
               
               
                   
                 U41078 
                 D26512 
               
               
                   
                 AF245447 
                 D28468 
                 515 
               
               
                   
                 AF245447 
                 D28468 
                 515 
               
               
                   
                 AA070997 
                 D29012 
                 43 
               
               
                   
                 2134847H1 
                 D30756 
                 324 
               
               
                   
                 AI147295 
                 D30756 
                 428 
               
               
                   
                 AA455067 
                 D31839 
                 23 
               
               
                   
                 AI311090 
                 D38616 
                 555 
               
               
                   
                 AW629690 
                 D42084 
                 794 
               
               
                   
                 1869911H1 
                 D42084 
                 692 
               
               
                   
                 5122374H1 
                 D43701 
                 719 
               
               
                   
                 D43950 
                 D43950 
                 106 
               
               
                   
                 D45887 
                 D45887 
                 437 
               
               
                   
                 W68193 
                 D49489 
               
               
                   
                 X72498 
                 D50326 
                 282 
               
               
                   
                 L11667 
                 D63861 
                 110 
               
               
                   
                 D63874 
                 D63874 
                 140 
               
               
                   
                 3633286H1 
                 D63874 
                 415 
               
               
                   
                 X61598 
                 D83174 
               
               
                   
                 AA279906 
                 D86550 
                 481 
               
               
                   
                 AA729988 
                 D86550 
                 752 
               
               
                   
                 D86956 
                 D86956 
               
               
                   
                 L36719 
                 D87116 
                 440 
               
               
                   
                 D89078 
                 D89078 
                 107 
               
               
                   
                 U41070 
                 D89078 
                 75 
               
               
                   
                 AI821897 
                 D89675 
                 789 
               
               
                   
                 D90209 
                 D90209 
                 141 
               
               
                   
                 2135769H1 
                 J02763 
                 350 
               
               
                   
                 J03040 
                 J03040 
                 438 
               
               
                   
                 1876511H1 
                 J03072 
                 643 
               
               
                   
                 J03258 
                 J03258 
                 120 
               
               
                   
                 J03571 
                 J03571 
                 296 
               
               
                   
                 J04111 
                 J04111 
                 157 
               
               
                   
                 AI125073 
                 J04132 
                 541 
               
               
                   
                 1634342H1 
                 J04794 
                 677 
               
               
                   
                 H30357 
                 J05451 
                 800 
               
               
                   
                 K02054 
                 K02054 
                 297 
               
               
                   
                 X02415 
                 K02569 
                 255 
               
               
                   
                 K03000 
                 K03000 
                 160 
               
               
                   
                 H58873 
                 K03195 
                 149 
               
               
                   
                 AI791949 
                 K03474 
                 567 
               
               
                   
                 L10413 
                 L00634 
                 164 
               
               
                   
                 H22919 
                 L03558 
                 143 
               
               
                   
                 L04288 
                 L04288 
               
               
                   
                 AA405769 
                 L05144 
                 30 
               
               
                   
                 H62473 
                 L07594 
                 150 
               
               
                   
                 L08177 
                 L08177 
                 109 
               
               
                   
                 L08177 
                 L08177 
                 109 
               
               
                   
                 AA234897 
                 L08895 
                 36 
               
               
                   
                 AA464627 
                 L09604 
                 18 
               
               
                   
                 M94859 
                 L10284 
                 222 
               
               
                   
                 R78541 
                 L10717 
               
               
                   
                 L15189 
                 L11066 
               
               
                   
                 M15400 
                 L11910 
                 171 
               
               
                   
                 L12168 
                 L12168 
                 439 
               
               
                   
                 L12350 
                 L12350 
                 298 
               
               
                   
                 L12350 
                 L12350 
                 298 
               
               
                   
                 T87908 
                 L12387 
                 452 
               
               
                   
                 L09600 
                 L13974 
               
               
                   
                 M14221 
                 L16510 
                 103 
               
               
                   
                 M60278 
                 L17032 
                 301 
               
               
                   
                 M60278 
                 L17032 
                 301 
               
               
                   
                 M60278 
                 L17032 
                 301 
               
               
                   
                 M60278 
                 L17032 
                 301 
               
               
                   
                 2745317H1 
                 L17411 
                 653 
               
               
                   
                 M65128 
                 L18980 
                 84 
               
               
                   
                 W49672 
                 L20861 
                 249 
               
               
                   
                 AI380522 
                 L23822 
                 552 
               
               
                   
                 AA988469 
                 L25591 
                 526 
               
               
                   
                 NM_001168 
                 L26245 
                 445 
               
               
                   
                 R20939 
                 L31848 
                 618 
               
               
                   
                 2470939H1 
                 L35848 
                 830 
               
               
                   
                 AA442810 
                 L36034 
                 502 
               
               
                   
                 L36148 
                 L36148 
                 113 
               
               
                   
                 M11723 
                 L43615 
                 101 
               
               
                   
                 M14745 
                 M14745 
                 170 
               
               
                   
                 W68291 
                 M15395 
                 250 
               
               
                   
                 M16038 
                 M16038 
               
               
                   
                 339598H1 
                 M16038 
               
               
                   
                 M17783 
                 M17783 
                 176 
               
               
                   
                 3171275H1 
                 M20199 
                 683 
               
               
                   
                 5189380H1 
                 M21121 
                 734 
               
               
                   
                 4130807F7 
                 M22440 
                 854 
               
               
                   
                 M22612 
                 M22612 
                 299 
               
               
                   
                 AA070627 
                 M22810 
                 421 
               
               
                   
                 1445982H1 
                 M23254 
                 342 
               
               
                   
                 M28638 
                 M24906 
                 93 
               
               
                   
                 R45525 
                 M28215 
                 209 
               
               
                   
                 AI051962 
                 M28983 
                 762 
               
               
                   
                 736837R6 
                 M29696 
                 373 
               
               
                   
                 M29870 
                 M29870 
                 182 
               
               
                   
                 AI264247 
                 M30309 
                 876 
               
               
                   
                 1512407F6 
                 M30310 
                 629 
               
               
                   
                 M30471 
                 M30471 
                 184 
               
               
                   
                 M30704 
                 M30703 
                 185 
               
               
                   
                 AW467649 
                 M31158 
                 435 
               
               
                   
                 M84739 
                 M32294 
               
               
                   
                 M84739 
                 M32294 
               
               
                   
                 U52165 
                 M32315 
                 241 
               
               
                   
                 M35857 
                 M32315 
                 189 
               
               
                   
                 5077322H1 
                 M32315 
                 416 
               
               
                   
                 N72918 
                 M34175 
                 198 
               
               
                   
                 M63193 
                 M58602 
                 443 
               
               
                   
                 M59465 
                 M59465 
                 193 
               
               
                   
                 2294719H1 
                 M60858 
                 352 
               
               
                   
                 2992331H1 
                 M63005 
                 839 
               
               
                   
                 AA069596 
                 M63582 
                 42 
               
               
                   
                 M63904 
                 M63904 
                 83 
               
               
                   
                 AI091579 
                 M63971 
                 518 
               
               
                   
                 M74782 
                 M74782 
                 216 
               
               
                   
                 AA410680 
                 M77016 
                 31 
               
               
                   
                 M80647 
                 M80647 
                 218 
               
               
                   
                 M84526 
                 M84526 
                 88 
               
               
                   
                 S93414 
                 M86553 
                 78 
               
               
                   
                 AI310138 
                 M91463 
                 549 
               
               
                   
                 M95678 
                 M95678 
                 223 
               
               
                   
                 2017923F6 
                 M96326 
                 825 
               
               
                   
                 R60624 
                 NM_000702 
               
               
                   
                 AA488324 
                 NM_001211 
                 388 
               
               
                   
                 AA488341 
                 NM_001336 
                 386 
               
               
                   
                 AF006823 
                 NM_002246 
               
               
                   
                 1322305T6 
                 NM_002250 
                 332 
               
               
                   
                 AI921879 
                 NM_002287 
                 574 
               
               
                   
                 AW129770 
                 NM_002349 
                 588 
               
               
                   
                 AJ004977 
                 NM_002873 
                 134 
               
               
                   
                 AI423526 
                 NM_003332 
                 559 
               
               
                   
                 4516963H1 
                 NM_003576 
                 710 
               
               
                   
                 3028719F6 
                 NM_003600 
                 680 
               
               
                   
                 AB010882 
                 NM_003601 
                 123 
               
               
                   
                 AF030424 
                 NM_003642 
                 126 
               
               
                   
                 AF029899 
                 NM_003814 
                 397 
               
               
                   
                 AF055993 
                 NM_003864 
                 131 
               
               
                   
                 AI220935 
                 NM_004142 
                 765 
               
               
                   
                 AW665782 
                 NM_004142 
                 616 
               
               
                   
                 AI191941 
                 NM_004226 
                 534 
               
               
                   
                 1392516T6 
                 NM_004621 
                 333 
               
               
                   
                 AA449579 
                 NM_004769 
                 116 
               
               
                   
                 1810447H1 
                 NM_004917 
                 321 
               
               
                   
                 AA047585 
                 NM_005109 
                 477 
               
               
                   
                 4181072F6 
                 NM_005468 
                 856 
               
               
                   
                 AA448972 
                 NM_005592 
                 503 
               
               
                   
                 AA742351 
                 NM_005739 
                 754 
               
               
                   
                 3406436F6 
                 NM_005845 
               
               
                   
                 AJ001015 
                 NM_005854 
                 104 
               
               
                   
                 3118530H1 
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                 NM_012089 
               
               
                   
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                 NM_012105 
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                 NM_012226 
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                 NM_013308 
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                 NM_013439 
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                 NM_014322 
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                 NM_014331 
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                 NM_014358 
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                 NM_014413 
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                 NM_014834 
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                 NM_014959 
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                 NM_014967 
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                 NM_015542 
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                 NM_015596 
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                 NM_015938 
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                 NM_016205 
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                 NM_016625 
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                 NM_017414 
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                 NM_017903 
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                 NM_018155 
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                 NM_018404 
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                 NM_018834 
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                 NM_018983 
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                 NM_019020 
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                 NM_020126 
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                 NM_020126 
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                 NM_020344 
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                 NM_021624 
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                 NM_021634 
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                 NM_022048 
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                 NM_022054 
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                 NM_022336 
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                 NM_023930 
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                 NM_024022 
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                 NM_024083 
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                 NM_024116 
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                 NM_024586 
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                 NM_024671 
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                 NM_024850 
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                 NM_030779 
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                 NM_030779 
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                 NM_030811 
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                 NM_032177 
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                 NM_032294 
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                 AW612141 
                 NM_033050 
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                 AA417237 
                 NM_033225 
               
               
                   
                 AI740538 
                 NM_033280 
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                 M57703 
                 S63697 
                 190 
               
               
                   
                 780099H1 
                 S63912 
                 376 
               
               
                   
                 AA714835 
                 S67156 
                 878 
               
               
                   
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                 S76736 
                 491 
               
               
                   
                 AA521213 
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                 U39231 
                 S79852 
                 74 
               
               
                   
                 N77754 
                 S79873 
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                 U00672 
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                 U02478 
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                 U03019 
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                 U07563 
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                 U20536 
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                 U25128 
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                 U26174 
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                 U29171 
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                 U33429 
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                 4 
               
               
                   
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                 U48449 
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                 U62293 
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                 XM_016514 
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                 XM_027140 
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                 XM_031246 
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                 XM_031608 
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                 XM_032556 
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                 XM_033674 
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                 XM_033788 
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                 XM_036492 
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                 XM_037453 
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                 XM_040459 
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                 XM_041087 
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                 XM_042041 
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                 XM_042637 
                 578 
               
               
                   
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                 XM_045320 
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                 XM_046411 
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                 XM_046691 
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                 XM_047328 
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                 XM_048530 
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                 XM_049228 
                 469 
               
               
                   
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                 XM_049755 
                 722 
               
               
                   
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                 XM_050250 
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                 L42856 
                 XM_054964 
                 168 
               
               
                   
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                 XM_056259 
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                 XM_058135 
                 548 
               
               
                   
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                 152 
               
               
                   
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                 290 
               
               
                   
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                 92 
               
               
                   
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                 Y13834 
                 458 
               
               
                   
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                 Z13009 
                 154 
               
               
                   
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                 Z15005 
                 34 
               
               
                   
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                 Z23115 
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                 Z26652 
                 797 
               
               
                   
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                 295 
               
               
                   
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                 Z32684 
                 632 
               
               
                   
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                 Z35481 
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                 Z48810 
                 55 
               
               
                   
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                 Z49148 
                 455 
               
               
                   
                 R70234 
                 Z56852 
                 446 
               
               
                   
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                 Z69918 
                 716 
               
               
                   
                 150224T6 
                 Z80147 
               
               
                   
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                 Z82188 
                 183 
               
               
                   
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                 Z82214 
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                 Z83821 
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                 Z83843 
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                 Z97832 
                 717 
               
               
                   
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                 Z98749 
               
               
                   
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                 Z98750 
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                 Z98752 
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                 Z98946 
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                 869 
               
               
                   
                 AA188574 
                   
                 480 
               
               
                   
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                 465 
               
               
                   
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                 391 
               
               
                   
                 AA460392 
                   
                 504 
               
               
                   
                 AA508510 
                   
                 472 
               
               
                   
                 AA515469 
                   
                 5 
               
               
                   
                 AA526772 
                   
                 474 
               
               
                   
                 AA576785 
                   
                 510 
               
               
                   
                 AA634241 
                   
                 486 
               
               
                   
                 AA663307 
                   
                 748 
               
               
                   
                 AA663482 
                   
                 749 
               
               
                   
                 AA713864 
                   
                 751 
               
               
                   
                 AA714520 
                   
                 489 
               
               
                   
                 AA828809 
                   
                 493 
               
               
                   
                 AA868502 
                   
                 883 
               
               
                   
                 AI061445 
                   
                 538 
               
               
                   
                 AI086865 
                   
                 540 
               
               
                   
                 AI264420 
                   
                 545 
               
               
                   
                 AI378131 
                   
                 888 
               
               
                   
                 AI440504 
                   
                 772 
               
               
                   
                 AI567491 
                   
                 776 
               
               
                   
                 AI693066 
                   
                 782 
               
               
                   
                 AI709066 
                   
                 784 
               
               
                   
                 AI766478 
                   
                 580 
               
               
                   
                 AI821337 
                   
                 572 
               
               
                   
                 AI949694 
                   
                 592 
               
               
                   
                 AW439329 
                   
                 792 
               
               
                   
                 AW630054 
                   
                 598 
               
               
                   
                 H24679 
                   
                 633 
               
               
                   
                 H29257 
                   
                 799 
               
               
                   
                 H51856 
                   
                 602 
               
               
                   
                 H66015 
                   
                 636 
               
               
                   
                 H72339 
                   
                 801 
               
               
                   
                 N57580 
                   
                 805 
               
               
                   
                 N54592 
                   
                 804 
               
               
                   
                 W07570 
                   
                 667 
               
               
                   
                 T75463 
                   
                 900 
               
               
                   
                 R88730 
                   
                 808 
               
               
                   
                 R91509 
                   
                 809 
               
               
                   
                 T56441 
                   
                 621 
               
               
                   
                 T77711 
                   
                 666 
               
               
                   
                 W92423 
                   
                 671 
               
               
                   
                 1274737F6 
                   
                 672 
               
               
                   
                 1338107F6 
                   
                 673 
               
               
                   
                 1508571F6 
                   
                 675 
               
               
                   
                 1548205H1 
                   
                 344 
               
               
                   
                 1594182F6 
                   
                 819 
               
               
                   
                 1594701F6 
                   
                 641 
               
               
                   
                 1879290H1 
                   
                 823 
               
               
                   
                 1902928H1 
                   
                 644 
               
               
                   
                 194370H1 
                   
                 322 
               
               
                   
                 195337H1 
                   
                 347 
               
               
                   
                 198381H1 
                   
                 323 
               
               
                   
                 2021568H1 
                   
                 693 
               
               
                   
                 205203T6 
                   
                 694 
               
               
                   
                 2194064H1 
                   
                 826 
               
               
                   
                 224922R6 
                   
                 696 
               
               
                   
                 2398102H1 
                   
                 647 
               
               
                   
                 2531082H1 
                   
                 698 
               
               
                   
                 2630745F6 
                   
                 651 
               
               
                   
                 264639H1 
                   
                 329 
               
               
                   
                 2704982H1 
                   
                 313 
               
               
                   
                 2716787H1 
                   
                 700 
               
               
                   
                 2798810F6 
                   
                 835 
               
               
                   
                 2832401H1 
                   
                 655 
               
               
                   
                 2894096F6 
                   
                 837 
               
               
                   
                 2919406F6 
                   
                 702 
               
               
                   
                 2937644F6 
                   
                 838 
               
               
                   
                 2950021H1 
                   
                 678 
               
               
                   
                 3010621F6 
                   
                 679 
               
               
                   
                 3123948H1 
                   
                 841 
               
               
                   
                 3253054R6 
                   
                 843 
               
               
                   
                 3290073H1 
                   
                 685 
               
               
                   
                 3330472H1 
                   
                 844 
               
               
                   
                 335737H1 
                   
                 362 
               
               
                   
                 3674358H1 
                   
                 688 
               
               
                   
                 3749346F6 
                   
                 848 
               
               
                   
                 3820429H1 
                   
                 690 
               
               
                   
                 3978404F6 
                   
                 849 
               
               
                   
                 4031124H1 
                   
                 707 
               
               
                   
                 4056384H1 
                   
                 708 
               
               
                   
                 4097060H1 
                   
                 853 
               
               
                   
                 4288779H1 
                   
                 726 
               
               
                   
                 4301823H1 
                   
                 727 
               
               
                   
                 4558488F6 
                   
                 712 
               
               
                   
                 4570377H1 
                   
                 729 
               
               
                   
                 5058893F9 
                   
                 733 
               
               
                   
                 5541621H1 
               
               
                   
                 5546249F6 
                   
                 740 
               
               
                   
                 5546336H1 
                   
                 860 
               
               
                   
                 5771839H1 
                   
                 862 
               
               
                   
                 5804485H1 
                   
                 863 
               
               
                   
                 5849807H1 
                   
                 371 
               
               
                   
                 6530555H1 
                   
                 866 
               
               
                   
                 656258H1 
                   
                 372 
               
               
                   
                 6591535H1 
                   
                 745 
               
               
                   
                 859993H1 
                   
                 310 
               
               
                   
                 930273R6 
                   
                 743 
               
               
                   
                 938765H1 
                   
                 379 
               
               
                   
                   
               
             
          
         
       
     
         [0077]    
       
         
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                   
               
               
                 Genes (By Genbank Accession Number) 
               
               
                 modulated at least 1.5 fold in all cell lines and 
               
               
                 at least 1.7 fold in patient responder sample. 
               
             
          
           
               
                   
                 Gene ID 
                 Accession No. 
                 Seq ID 
               
               
                   
                   
               
             
          
           
               
                   
                 5543360F8 
                 AC009220 
                 738 
               
               
                   
                 AA237071 
                 AL035420 
                 467 
               
               
                   
                 AA455969 
                 D00015 
                 20 
               
               
                   
                 M25315 
                 D12592 
                 90 
               
               
                   
                 U41078 
                 D26512 
               
               
                   
                 L10413 
                 L00634 
                 164 
               
               
                   
                 AA464627 
                 L09604 
                 18 
               
               
                   
                 2470939H1 
                 L35848 
                 830 
               
               
                   
                 M84526 
                 M84526 
                 88 
               
               
                   
                 AI921879 
                 NM_002287 
                 574 
               
               
                   
                 AF204944 
                 NM_012105 
                 527 
               
               
                   
                 W77977 
                 NM_022336 
                 815 
               
               
                   
                 AA449040 
                 NM_024116 
                 483 
               
               
                   
                 AA521213 
                 S77359 
                 473 
               
               
                   
                 AA984230 
                 S80071 
                 524 
               
               
                   
                 AA456616 
                 U14970 
                 22 
               
               
                   
                 AI884916 
                 U29171 
                 591 
               
               
                   
                 U60519 
                 U60519 
                 62 
               
               
                   
                 X00351 
                 X13839 
                 251 
               
               
                   
                 AA868186 
                 X17093 
                 425 
               
               
                   
                 H27379 
                 X57198 
                 144 
               
               
                   
                 AA454585 
                 X75755 
                 2 
               
               
                   
                 X89576 
                 X89576 
                 51 
               
               
                   
                 AI580830 
                 XM_042041 
                 562 
               
               
                   
                 U49083 
                 Z49148 
                 455 
               
               
                   
                 2398102H1 
                   
                 647 
               
               
                   
                 2531082H1 
                   
                 698 
               
               
                   
                   
               
             
          
         
       
     
         [0078]