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 U.S. Provisional applications: 60/340,938; 60/338,997; 60/340,081; and 60/341,012. 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 myclogenous 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 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.  
           [0009]    In yet another aspect of the invention, the FTI is a quinilone or quinoline derivative.  
           [0010]    In yet another aspect of the invention, the FTI is (B)-6-[amino(420 chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone).  
           [0011]    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.  
           [0012]    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.  
           [0013]    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.  
           [0014]    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  
       [0015]    [0015]FIG. 1 is an example of a graphical display of gene expression patterns used to analyze the gene expression profiles of this invention.  
         [0016]    [0016]FIG. 2 is a schematic diagram of the MAPK/ERK pathway.  
         [0017]    [0017]FIG. 3 is a schematic diagram of the TGFβ and Wnt pathway.  
         [0018]    [0018]FIG. 4 is a schematic diagram of the apoptotic pathway. 
     
    
     DETAILED DESCRIPTION  
       [0019]    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.  
         [0020]    Numerous FTIs are within the scope of the invention and include those described in U.S. Patents: 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 de Solms 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:  
         [0021]    7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one,  
         [0022]    7-(3-chlorophenyl)-9-[(4-chlorophenyl)-1H-imidazol-1-ylmethyl]-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-4-one,  
         [0023]    8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chlorophen yl)-1,2-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-4-one, and  
         [0024]    8-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-6-(3-chloropheny l)-2,3-dihydro-1H,5H-benzo[ij]quinolizin-5-one.  
         [0025]    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 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.  
         [0032]    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 FTIs. Portfolios of gene expression profiles can be comprised of combinations of genes shown in Tables 1-3.  
         [0033]    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.  
         [0034]    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.  
         [0035]    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.  
         [0036]    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.  
         [0037]    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.  
         [0038]    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.  
         [0039]    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  
         [0040]    where: A, B, C, D are genes  
         [0041]    ++up-regulates  
         [0042]    −−down-regulates  
         [0043]    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.  
         [0044]    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.  
         [0045]    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 FTIs 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.  
         [0046]    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.  
         [0047]    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.  
         [0048]    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.  
         [0049]    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.  
         [0050]    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.  
         [0051]    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, coadministration or sequential administration of other agents may be desirable.  
         [0052]    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.  
         [0053]    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.  
         [0054]    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., 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 polyvinylpyrrolidone, 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-i 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 CD33 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.  
       EXAMPLE 7  
     Differential Gene Expression in Treated Cell Line Samples  
       [0072]    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.  
         [0073]    Genes analyzed according to this invention are identified in the tables below by reference to Gene ID Numbers (internally generated) and accession numbers in the Genbank database where such genes have been entered in the Genbank database. The attached sequence listing, incorporated herein by reference, shows sequences corresponding to the Gene ID Number and are named with those Gene ID Numbers. In some cases, the listed sequences are 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. Further, it should be noted that some of the sequences in the listing contain the letter “N” in place of a nucleotide designation. One skilled in the art will recognize that the “N” indicates placement of any nucleotide in that portion of the sequence.  
       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.                       3434105F7   AB026898           3881595H1   AC000134           AI939481   AC005155           AA961061   AC005670           3918104H1   AC006023           AI025519   AC008427           5543360F8   AC009220           AA744682   AC009289           AA932129   AC009756           AI148008   AC011473           Y00052   AC013722           R52476   AC021078           AA864819   AC022087           AI815593   AC022150           AI141943   AC026448           AI300541   AC073585           2515486H1   AF161372           1731618H1   AJ003147           BE222911   AJ400879           R13802   AK022901           AI656222   AL021155           AI553823   AL022313           AA010251   AL034397           AA237071   AL035420           2445101F6   AL049824           AI638342   AL122004           AA779424   AL136980           H81171   AL137073           R77754   AL137790           AI209040   AL139082           6421806H1   AL139396           H61066   AL161787           R59209   AL355136           AA486141   AL355352           AI339252   AP001630           AW023438   BC009732           914979H1   BC013834           AA455969   D00015           T64335   D00017           X02308   D00596           X67098   D00596           X01023   D10493           D10493   D10493           Y00396   D10493           X69292   D10667           AA736561   D11094           S68252   D11139           M25315   D12592           AI186110   D13118           H84153   D13639           AA598561   D14043           D14695   D14695           2206642T6   D16889           AI878943   D17004           U38846   D17080           J03801   D21235           AI762926   D23660           D25215   D25215           U41078   D26512           AA485961   D30648           AA456408   D38441           AI311090   D38616           1869911H1   D42084           D43950   D43950           AW006368   D44467           U29092   D45050           D45887   D45887           W68193   D49489           3633286H1   D63874           N76967   D66904           AA985407   D82326           AI962797   D83260           M59829   D85730           3107995H1   D86322           AA279906   D86550           AI016874   D86586           556963H1   D86955           AI810687   D86997           AF045581   D87462           U41070   D89078           D90209   D90209           AA812265   D90767           2135769H1   J02763           1876511H1   J03072           J04088   J04088           AI590075   J04973           H30357   J05451           K00558   K03460           L10413   L00634           L01087   L01087           AI027898   L02426           L06139   L06139           U28936   L07914           M86400   L07955           AA428915   L08634           AA464627   L09604           M94859   L10284           R78541   L10717           L15189   L11066           L11284   L11284           T87908   L12387           T80827   L13802           L08044   L15203           AI278029   L16862           M60278   L17032           M60278   L17032           M65128   L18980           W49672   L20861           L22005   L22005           AI380522   L23822           AA988469   L25591           L26336   L26336           AI074564   L32866           M63175   L35233           2470939H1   L35848           AA190648   L36055           AI243166   L38716           L39833   L39833           M97347   L41415           2005142H1   L42324           M11723   L43615           U04045   L47574           AA284067   L76938           M13142   M13142           W68291   M15395           5560880H1   M19483           3171275H1   M20199           M22489   M22489           AA070627   M22810           H39560   M24736           M25897   M25897           M27492   M27492           AA570304   M29366           205581R6   M29696           M84739   M32294           M84739   M32294           M35857   M32315           3801801H1   M33680           M63904   M63904           AI091579   M63971           M69215   M69215           M74782   M74782           M80254   M80254           M80647   M80647           M84526   M84526           6805226H1   M84526           S93414   M86553           M91556   M91556           M95678   M95678           2017923F6   M96326           H73054   NM_000551           AA488324   NM_001211           N73242   NM_001274           AF013611   NM_001335           AW163686   NM_001524           AI921879   NM_002287           AI652785   NM_002333           AI423526   NM_003332           3028719F6   NM_003600           AB010882   NM_003601           AF030424   NM_003642           AW194791   NM_003668           AF075599   NM_003969           AF031141   NM_004223           2676931T6   NM_004412           AF053304   NM_004725           AF119815   NM_004885           AI816398   NM_004888           2185556H1   NM_004917           3357511H1   NM_004917           AA047585   NM_005109           AA448972   NM_005592           AW629084   NM_005817           AJ001015   NM_005854           AJ001016   NM_005856           U85055   NM_006480           3618886F6   NM_006536           AA906714   NM_006573           AF060153   NM_007037           1467864F6   NM_012089           AI097079   NM_012100           AF204944   NM_012105           W44673   NM_012428           AI522316   NM_013386           AI700673   NM_013439           AA057781   NM_014172           AI299795   NM_014251           1931159F6   NM_014397           AW630208   NM_014413           2821685T6   NM_014967           1539060H1   NM_015343           AI762738   NM_015449           AA401397   NM_015596           AW243944   NM_015596           AI436551   NM_016141           AI651159   NM_016440           AA527334   NM_016625           g922698   NM_017555           1693028H1   NM_017636           002783H1   NM_017860           AI368583   NM_017874           AW170305   NM_017903           H62827   NM_018321           M78706   NM_019020           BE048230   NM_020216           AI214466   NM_020334           AA452802   NM_021196           AI808824   NM_022082           W77977   NM_022336           AA535015   NM_022570           AA861140   NM_022829           AW078834   NM_023080           5122087H1   NM_024056           AF017182   NM_024101           AA449040   NM_024116           2792728F6   NM_024902           BE218593   NM_025230           AA669885   NM_030763           AI339565   NM_030908           AF038564   NM_031483           AI126706   NM_032038           1961084H1   NM_032188           4609810F6   NM_032554           AA745592   NM_032844           AW612141   NM_033050           AI740538   NM_033280           U58522   S51016           M57703   S63697           AA873257   S73591           AA521213   S77359           N77754   S79873           AA984230   S80071           R79935   S81439           T71391   T71391           AA598776   U05340           U11053   U11053           T55353   U12597           AA456616   U14970           U18300   U18300           AF017306   U20657           AA459663   U25182           U27699   U27699           AI884916   U29171           U29171   U29171           1671033F6   U33429           AA017042   U40989           AI126520   U48405           U48807   U48807           U49395   U49395           AA186542   U50078           U51586   U51586           AW150605   U54558           AA455800   U55206           AF029777   U57316           I19355   U58913           319095H1   U58913           AF027964   U59911           U60519   U60519           AI371158   U65378           U69883   U69883           H30148   U73641           R80718   U75283           U77180   U77180           U78180   U78180           U83115   U83115           AA938905   U86218           AI401546   U88844           2526581H1   U90904           AA773114   U95740           AA176596   U96781           X13274   V00543           I16618   V00595           R91899   X00226           AW519155   X00318           X87344   X00369           X02910   X01394           M15840   X02532           AA401046   X02592           X02812   X02812           X87344   X03066           X03084   X03084           M10901   X03225           X03225   X03225           R81823   X03742           X04011   X04011           K02400   X04076           X07036   X04408           X07036   X04408           Y00816   X05309           N20475   X05344           M11233   X05344           X02544   X05784           X52192   X06292           R33755   X06547           X06989   X06989           X07979   X07979           X14723   X08004           M20566   X12830           M20566   X12830           X13197   X13197           M21304   X13709           X00351   X13839           X60236   X14008           H57180   X14034           M33011   X14758           X14768   X14768           M31625   X14768           M31626   X14768           M30816   X14768           X52882   X14983           AA598758   X15187           X15606   X15606           K03515   X16539           AA868186   X17093           X51416   X51416           M23699   X51439           AA455222   X51675           X51757   X51757           X52195   X52195           U06434   X53682           J03198   X54048           M32304   X54533           AA487812   X56134           X56134   X56134           M16985   X56257           N31660   X56257           H27379   X57198           X57522   X57522           X57830   X57830           M57765   X58377           X58528   X58528           M81182   X58528           S60489   X60111           AI739095   X61157           R76314   X61587           M83665   X62534           X65921   X65921           M37722   X66945           AA453816   X69516           AA187162   X69654           X69819   X69711           X70070   X70070           X70697   X70697           S40706   X71427           T53775   X71874           X71877   X71877           X73458   X73458           X74801   X74801           AA454585   X75755           R43734   X76939           AI189206   X77303           2496221H1   X77303           H17504   X80692           R26434   X80910           X83688   X83688           U24231   X84709           3576337H1   X85030           X87212   X87212           T56477   X87212           AA464034   X89401           X89576   X89576           AA187458   X92396           M15887   X94565           X94991   X94991           X96427   X96427           X97058   X97058           AA425120   X98262           3283686H1   XM_005825           AW027188   XM_005958           1525902F6   XM_006646           R48796   XM_008099           AK000599   XM_027140           AA044653   XM_031608           AW665954   XM_035574           H86407   XM_037453           R00285   XM_038150           X57447   XM_039395           778372H1   XM_040459           R82530   XM_041024           AI580830   XM_042041           3097063H1   XM_044784           3038910H1   XM_046691           H53340   XM_048213           1654210F6   XM_048530           L42856   XM_054964           2707270F6   XM_056259           M23468   Y00062           Y00649   Y00649           Y00757   Y00757           M17017   Y00787           M28130   Y00787           L02932   Y07619           Y10256   Y10256           AA454813   Y12395           AA149850   Y12670           704183H1   Y13710           059476H1   Y13829           Y13834   Y13834           L11016   Y14768           3141315H1   Y17803           AI341167   Y18391           AI707852   Z12962           U51278   Z23115           AI686653   Z26876           AA043102   Z35102           AA136533   Z35481           U49083   Z49148           R70234   Z56852           257274R6   Z58168           U62027   Z73157           391237F1   Z73157           510997F1   Z73157           AI808621   Z82214           AA460801   Z98749           2673259F6   Z98752           R22977   Z98946           L03380   Z99995           AA425422           AA460392           AA508510           AA552028           AA576785           AA663307           AI015248           AI024468           AI086865           AI190605           AI203269           AI264420           AI333013           AI435052           AI671268           AI796718           AI990816           AW027164           AW167520           H24679           H66015           H91370           W07570           1274737F6           195337H1           2398102H1           2531082H1           264639H1           2794246F6           3290073H1           335737H1           4539942F8           6300669H1           938765H1                      
 
         [0076]    [0076]                             TABLE 2                           Genes (by GenBank Accession Number) modulated       at least 1.7 fold in primary AML Sample.                Gene ID   Accession No.                       T94331   AB026898           3881595H1   AC000134           1329021F6   AC002073           2858615H1   AC002325           AI791539   AC002428           AI821217   AC004258           AA774798   AC004671           H29666   AC004845           T95173   AC005071           AA814523   AC005160           5905620T9   AC005212           5986963H1   AC005280           5825251H1   AC005306           N36113   AC005670           1700438H1   AC005682           R48756   AC005757           5538589F6   AC005839           3918104H1   AC006023           AA443719   AC007240           AI867297   AC007883           R63067   AC008073           AW022174   AC008382           5537789F6   AC008525           H00249   AC008733           1436240H1   AC008860           2668191F6   AC008949           5543360F8   AC009220           AA737674   AC009892           5104579H1   AC009892           3335217F6   AC010311           BE326380   AC010521           3746214H1   AC011088           1671315F6   AC011500           H60969   AC012351           AA926944   AC012377           3100089H1   AC012454           Y00052   AC013722           R52476   AC021078           N45149   AC021106           AI742120   AC022137           4177228F6   AC022224           2676312H1   AC022415           H73476   AC022740           AA652121   AC046170           AI308320   AC046170           1956982H1   AC046170           1428534F6   AC051619           2914934H1   AC055707           AA621370   AC064807           5514511R6   AC073333           AI698737   AC074331           3406131H1   AC079118           N20072   AC096579           5911413H1   AC096667           AI458182   AF042782           2291436H1   AF074333           W32067   AF136745           6755801J1   AF157623           2397317F6   AF235100           R53190   AF384819           1731618H1   AJ003147           2959801H1   AJ003147           3123232H1   AJ003147           2760110H1   AJ006345           X64073   AJ239325           3986782F7   AJ249275           AI366098   AJ276674           AI695385   AJ289236           BE222911   AJ400879           AI400473   AK017738           AI299633   AK021499           R13802   AK022901           1489075H1   AK025775           AI656222   AL021155           W96144   AL021155           2459540H1   AL031282           3461693F6   AL031588           4333034H1   AL031726           3332309H1   AL031728           R61661   AL032821           U71321   AL033519           AA935151   AL034374           AA010251   AL034397           U43431   AL035367           AA237071   AL035420           AA609779   AL049610           AA167461   AL049612           4228729H2   AL049742           6712339H1   AL049766           AI051176   AL049872           1747028H1   AL078600           5164454H1   AL109840           7007735H1   AL117382           AA526337   AL121601           AI638342   AL122004           4835576H1   AL122035           W01596   AL133243           U64205   AL133367           4820983H1   AL135786           5594552H1   AL136381           H12102   AL136979           H81171   AL137073           AA151374   AL137790           AA578089   AL138787           AI209040   AL139082           6421806H1   AL139396           H60498   AL157776           3721604H1   AL160271           H61066   AL161787           2798009H1   AL162252           2225447F6   AL162430           AI885557   AL162729           2918417F6   AL163279           AA489975   AL355151           U77456   AL355794           5375277T9   AL356266           AI051860   AL356489           4019605F6   AL356489           U29607   AL356801           AA861429   AL359512           AA767859   AL359915           1362587H1   AL391122           R09122   AL391194           R93094   AP000173           AA954331   AP000432           R10535   AP000555           5327443H1   AP000936           1569726H1   AP001347           R92422   AP001672           3422674H1   AP002800           AI310451   AP002812           3568042H1   AP003900           AA455969   D00015           AF030575   D00015           T64335   D00017           D12614   D00102           X67098   D00596           R27585   D00759           AA465593   D00762           M80436   D10202           M80436   D10202           M80436   D10202           M80436   D10202           AA464600   D10493           AI147046   D10653           S68252   D11139           M25315   D12592           AI186110   D13118           S57708   D13515           D13626   D13626           AA682625   D13641           AA598561   D14043           D14695   D14695           D14825   D14825           855326R1   D16234           L20046   D16305           V00496   D17206           AA629808   D17554           M57285   D21214           J03801   D21235           AI700360   D21878           D25216   D25216           U41078   D26512           AF245447   D28468           AF245447   D28468           AA070997   D29012           2134847H1   D30756           AI147295   D30756           AA455067   D31839           AI311090   D38616           AW629690   D42084           1869911H1   D42084           5122374H1   D43701           D43950   D43950           D45887   D45887           W68193   D49489           X72498   D50326           L11667   D63861           D63874   D63874           3633286H1   D63874           X61598   D83174           AA279906   D86550           AA729988   D86550           D86956   D86956           L36719   D87116           D89078   D89078           U41070   D89078           AI821897   D89675           D90209   D90209           2135769H1   J02763           J03040   J03040           1876511H1   J03072           J03258   J03258           J03571   J03571           J04111   J04111           AI125073   J04132           1634342H1   J04794           H30357   J05451           K02054   K02054           X02415   K02569           K03000   K03000           H58873   K03195           AI791949   K03474           L10413   L00634           H22919   L03558           L04288   L04288           AA405769   L05144           H62473   L07594           L08177   L08177           L08177   L08177           AA234897   L08895           AA464627   L09604           M94859   L10284           R78541   L10717           L15189   L11066           M15400   L11910           L12168   L12168           L12350   L12350           L12350   L12350           T87908   L12387           L09600   L13974           M14221   L16510           M60278   L17032           M60278   L17032           M60278   L17032           M60278   L17032           2745317H1   L17411           M65128   L18980           W49672   L20861           AI380522   L23822           AA988469   L25591           NM_001168   L26245           R20939   L31848           2470939H1   L35848           AA442810   L36034           L36148   L36148           M11723   L43615           M14745   M14745           W68291   M15395           M16038   M16038           339598H1   M16038           M17783   M17783           3171275H1   M20199           5189380H1   M21121           4130807F7   M22440           M22612   M22612           AA070627   M22810           1445982H1   M23254           M28638   M24906           R45525   M28215           AI051962   M28983           736837R6   M29696           M29870   M29870           AI264247   M30309           1512407F6   M30310           M30471   M30471           M30704   M30703           AW467649   M31158           M84739   M32294           M84739   M32294           U52165   M32315           M35857   M32315           5077322H1   M32315           N72918   M34175           M63193   M58602           M59465   M59465           2294719H1   M60858           2992331H1   M63005           AA069596   M63582           M63904   M63904           AI091579   M63971           M74782   M74782           AA410680   M77016           M80647   M80647           M84526   M84526           S93414   M86553           AI310138   M91463           M95678   M95678           2017923F6   M96326           R60624   NM_000702           AA488324   NM_001211           AA488341   NM_001336           AF006823   NM_002246           1322305T6   NM_002250           AI921879   NM_002287           AW129770   NM_002349           AJ004977   NM_002873           AI423526   NM_003332           4516963H1   NM_003576           3028719F6   NM_003600           AB010882   NM_003601           AF030424   NM_003642           AF029899   NM_003814           AF055993   NM_003864           AI220935   NM_004142           AW665782   NM_004142           AI191941   NM_004226           1392516T6   NM_004621           AA449579   NM_004769           1810447H1   NM_004917           AA047585   NM_005109           4181072F6   NM_005468           AA448972   NM_005592           AA742351   NM_005739           3406436F6   NM_005845           AJ001015   NM_005854           3118530H1   NM_005880           AA906714   NM_006573           AI016020   NM_006672           AW770551   NM_006770           AW009940   NM_006871           864164H1   NM_007194           1467864F6   NM_012089           AF204944   NM_012105           W23427   NM_012115           3363678H2   NM_012226           AI652076   NM_012243           346874T6   NM_013308           AI522316   NM_013386           AI338030   NM_013439           AI700673   NM_013439           4540025H1   NM_014322           W00842   NM_014331           AW511388   NM_014358           AW630208   NM_014413           H63640   NM_014834           AI743175   NM_014959           2821685T6   NM_014967           W38474   NM_015542           AW243944   NM_015596           W07181   NM_015701           2997457H1   NM_015938           AA631149   NM_016205           AA527334   NM_016625           5543749F6   NM_017414           AW170305   NM_017903           AA160974   NM_018155           AA625433   NM_018404           AA074666   NM_018834           767295H1   NM_018983           M78706   NM_019020           AF245447   NM_020126           AF245447   NM_020126           4294821H1   NM_020344           2490994H1   NM_021624           3556218H1   NM_021634           2435705R6   NM_022048           3092423H1   NM_022054           W77977   NM_022336           AA429219   NM_023930           1001514R6   NM_024022           AI031531   NM_024083           AA449040   NM_024116           2803571H1   NM_024586           1390130H1   NM_024671           3241088H1   NM_024850           H96170   NM_030779           1540906H1   NM_030779           AI824146   NM_030811           W90438   NM_032127           AA430653   NM_032177           3495438F6   NM_032294           AW612141   NM_033050           AA417237   NM_033225           AI740538   NM_033280           M57703   S63697           780099H1   S63912           AA714835   S67156           AA777347   S76736           AA521213   S77359           U39231   S79852           N77754   S79873           AA984230   S80071           U00672   U00672           U02478   U02478           AA019459   U02680           3401107H1   U03019           AI580044   U04816           3041874H1   U07563           2457652H1   U12465           U39318   U13175           U13666   U13666           U13695   U13695           AA056652   U14176           AA456616   U14970           U18242   U18242           U18300   U18300           AA465444   U18422           U20537   U20536           U25128   U25128           U35237   U26174           AI884916   U29171           AA481076   U31278           NM_002411   U33147           1671033F6   U33429           AA664389   U35048           6313632H1   U43030           R09288   U43522           AA488645   U47007           U47077   U47077           5801413H1   U48449           2405358R6   U48729           AA186542   U50078           U51586   U51586           1355140F1   U51586           AA455800   U55206           U56390   U56390           U83410   U58088           AA121261   U58675           AF027964   U59911           U60519   U60519           2836805T6   U62293           U62433   U62433           3188135H1   U66673           3188135H1   U66673           3188135H1   U66673           3188135H1   U66673           1360938T6   U66679           809631T6   U66684           AA454652   U67058           AI214335   U68755           U69883   U69883           R98589   U81375           5695322H1   U82671           AA745989   U82979           AA188256   U83661           2526581H1   U90904           AA434064   U95000           AA773114   U95740           AA514978   U96776           Y07503   V00510           X96754   V00557           N67917   V01512           V01514   V01514           X87344   X00369           N53169   X00567           X02910   X01394           X01451   X01451           X01451   X01451           X01451   X01451           X01451   X01451           AA401046   X02592           5537736F6   X02592           X87344   X03066           M10901   X03225           M54894   X04403           M54894   X04403           M54894   X04403           M54894   X04403           X07036   X04408           X07036   X04408           N75719   X04744           M19507   X04876           Y00816   X05309           M11233   X05344           AA479102   X05972           N24824   X06182           R33755   X06547           N41062   X06820           M86511   X06882           X07549   X07549           1686702H1   X07730           X07979   X07979           X14723   X08004           J03561   X12510           J03561   X12510           J03561   X12510           J03561   X12510           M20566   X12830           M20566   X12830           M20566   X12830           M20566   X12830           U76549   X12882           M21304   X13709           X00351   X13839           X14830   X14830           X52882   X14983           AA598758   X15187           H27564   X15729           W15277   X15940           AA393214   X15949           M23502   X16166           K03515   X16539           M28880   X166P9           2403512H1   X16674           AA868186   X17093           J03236   X51345           X51416   X51416           AA411440   X51521           AA058828   X51602           AA455222   X51675           X51804   X51804           T72877   X52015           X52195   X52195           X52947   X52947           U06434   X53682           3081284F6   X53702           M36821   X53799           AA490256   X54048           J03198   X54048           M60761   X54228           M11025   X55283           M33294   X55313           M33294   X55313           M31627   X55543           X55544   X55544           AA487812   X56134           X56134   X56134           X56777   X56777           H27379   X57198           M83652   X57748           X58528   X58528           M81182   X58528           S60489   X60111           X60592   X60592           R76314   X61587           M83665   X62534           R11490   X62947           AI436567   X63422           X63465   X63465           AA083577   X63527           X63547   X63546           2159360H1   X63692           X64074   X63926           X63926   X63926           X64083   X63926           2535659H1   X69168           AA187162   X69654           X69819   X69711           AI310990   X71491           T53775   X71874           3285272H1   X73568           U11087   X75299           X75299   X75299           AA454585   X75755           X75821   X75821           X75918   X75918           X76029   X76029           R43734   X76939           AI189206   X77303           H17504   X80692           R26434   X80910           AI521155   X81892           AA088861   X83228           U10440   X84849           407169H1   X84909           3576337H1   X85030           T55802   X85117           4407508H1   X85337           AA025432   X85373           T56477   X87212           AA464034   X89401           X89576   X89576           X89576   X89576           R83270   X89750           917064H1   X91249           X91809   X91809           X92106   X92106           AA187458   X92396           AJ000519   X92962           X94991   X94991           X96427   X96427           R85213   X98022           X98296   X98296           X99585   X99585           R48796   XM_008099           R50354   XM_009915           W15172   XM_016514           AK000599   XM_027140           7157414H1   XM_031246           AA044653   XM_031608           L16953   XM_032556           1266202T6   XM_033674           AA805691   XM_033788           AA861582   XM_036492           H86407   XM_037453           778372H1   XM_040459           AA016239   XM_041087           AI580830   XM_042041           AI732875   XM_042637           AA463411   XM_045320           AA648280   XM_046411           3038910H1   XM_046691           H63831   XM_047328           1654210F6   XM_048530           AA460131   XM_049228           5539620F6   XM_049755           AA682896   XM_050250           L42856   XM_054964           1483347H1   XM_056259           AI307255   XM_058135           H74265   Y00062           Y00064   Y00064           M17017   Y00787           M28130   Y00787           L02932   Y07619           AA504415   Y09781           AI809036   Y12336           AA516206   Y12851           000527H1   Y13829           059476H1   Y13829           Y13834   Y13834           L11016   Y14768           3141315H1   Y17803           551234R6   Y17803           AA426103   Y18000           H97778   Z13009           AA402431   Z15005           L07555   Z22576           U51278   Z23115           M58525   Z26491           AW772610   Z26652           Z29090   Z29090           H19371   Z32684           AA136533   Z35481           Z48810   Z48810           U49083   Z49148           R70234   Z56852           4902714H1   Z69918           150224T6   Z80147           M29871   Z82188           AI808621   Z82214           AA699919   Z83821           5538394H1   Z83843           5020377F9   Z97832           AA460801   Z98749           AI625585   Z98750           2673259F6   Z98752           R22977   Z98946           AA007595           AA188574           AA280754           AA283874           AA460392           AA508510           AA515469           AA526772           AA576785           AA634241           AA663307           AA663482           AA713864           AA714520           AA828809           AA868502           AI061445           AI086865           AI264420           AI378131           AI440504           AI567491           AI693066           AI709066           AI766478           AI821337           AI949694           AW439329           AW630054           H24679           H29257           H51856           H66015           H72339           N57580           N54592           W07570           T75463           R88730           R91509           T56441           T77711           W92423           1274737F6           1338107F6           1508571F6           1548205H1           1594182F6           1594701F6           1879290H1           1902928H1           194370H1           195337H1           198381H1           2021568H1           205203T6           2194064H1           224922R6           2398102H1           2531082H1           2630745F6           264639H1           2704982H1           2716787H1           2798810F6           2832401H1           2894096F6           2919406F6           2937644F6           2950021H1           3010621F6           3123948H1           3253054R6           3290073H1           3330472H1           335737H1           3674358H1           3749346F6           3820429H1           3978404F6           4031124H1           4056384H1           4097060H1           4288779H1           4301823H1           4558488F6           4570377H1           5058893F9           5541621H1           5546249F6           5546336H1           5771839H1           5804485H1           5849807H1           6530555H1           656258H1           6591535H1           859993H1           930273R6           938765H1                        
         [0077]    [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.                       5543360F8   AC009220           AA237071   AL035420           AA455969   D00015           M25315   D12592           U41078   D26512           L10413   L00634           AA464627   L09604           2470939H1   L35848           M84526   M84526           AI921879   NM_002287           AF204944   NM_012105           W77977   NM_022336           AA449040   NM_024116           AA521213   S77359           AA984230   S80071           AA456616   U14970           AI884916   U29171           U60519   U60519           X00351   X13839           AA868186   X17093           H27379   X57198           AA454585   X75755           X89576   X89576           AI580830   XM_042041           U49083   Z49148           2398102H1           2531082H1                        
         [0078]    [0078] 
     
       
       
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                 SEQUENCE LISTING 
               
             
          
           
               
                 The patent application contains a lengthy “Sequence Listing” section. A copy of the “Sequence Listing” is available in electronic form from the USPTO 
               
               
                 web site (http://seqdata.uspto.gov/sequence.html?DocID=20040110792). An electronic copy of the “Sequence Listing” will also be available from the 
               
               
                 USPTO upon request and payment of the fee set forth in 37 CFR 1.19(b)(3).