bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adult Patients With De Novo Acute Myeloid Leukemia and t(9; 11)(p22; q23) Have a Superior Outcome to Patients With Other Translocations Involving Band 11q23: A Cancer and Leukemia Group B Study
Authors: Mrózek Krzysztof , Heinonen Kristiina , Lawrence David , Carroll Andrew J. , Koduru Prasad R.K. , Rao Kathleen W. , Strout Matthew P. , Hutchison Robert E. , Moore Joseph O. , Mayer Robert J. , Schiffer Charles A. , Bloomfield Clara D. 
Published: October 2019

Abstract
Following reports of childhood acute myeloid leukemia (AML) showing that patients with t(9; 11)(p22; q23) have a better prognosis than those with translocations between 11q23 and other chromosomes, we compared response to therapy and survival of 24 adult de novo AML patients with t(9; 11) with those of 23 patients with other 11q23 translocations [t(11q23)]. Apart from a higher proportion of French-American-British (FAB) M5 subtype in the t(9; 11) group (83% v 43%, P = .006), the patients with t(9; 11) did not differ significantly from patients with t(11q23) in terms of their presenting clinical or hematologic features. Patients with t(9; 11) more frequently had an extra chromosome(s) 8 or 8q as secondary abnormalities (46% v 9%, P = .008). All patients received standard cytarabine and daunorubicin induction therapy, and most of them also received cytarabine-based intensification treatment. Two patients, both with t(9; 11), underwent bone marrow transplantation (BMT) in first complete remission (CR). Nineteen patients (79%) with t(9; 11) and 13 (57%) with t(11q23) achieved a CR (P = .13). The clinical outcome of patients with t(9; 11) was significantly better: the median CR duration was 10.7 versus 8.9 months (P = .02), median event-free survival was 6.2 versus 2.2 months (P = .009), and median survival was 13.2 versus 7.7 months (P = .009). All patients with t(11q23) have died, whereas seven (29%) patients with t(9; 11) remain alive in first CR. Seven of eight patients with t(9; 11) who received postremission regimens with cytarabine at a dose of 100 (four patients) or 400 mg/m2 (2 patients) or who did not receive postremission therapy (2 patients) have relapsed. In contrast, 7 (64%) of 11 patients who received intensive postremission chemotherapy with high-dose cytarabine (at a dose 3 g/m2) (5 patients), or underwent BMT (2 patients) remain in continuous CR. We conclude that the outcome of adults with de novo AML and t(9; 11) is more favorable than that of adults with other 11q23 translocations; this is especially true for t(9; 11) patients who receive intensive postremission therapy.
Development of a Candidate HLA A*0201 Restricted Peptide-Based Vaccine Against Human Cytomegalovirus Infection
Authors: Diamond Don J. , York Joanne , Sun Ji-Yao , Wright Christine L. , Forman Stephen J. 
Published: October 2019

AbstractThe development of a protective cellular immune response against human cytomegalovirus (HCMV) is the most important determinant of recovery from HCMV infection after allogeneic bone marrow transplantation (BMT). The ultimate aim of our study is to develop an antigen-specific and peptide-based vaccine strategy against HCMV in the setting of BMT. Toward this end we have studied the cellular immune response against the immunodominant matrix protein pp65 of HCMV. Using an HLA A*0201-restricted T-cell clone reactive against pp65 from peripheral blood from a seropositive individual, we have mapped the position of the cytolytic T lymphocyte (CTL) epitope from HCMV pp65 to an 84-amino acid segment. Of the four peptides which best fit the HLA A*0201 motif in that region, one nonamer sensitized an autologous Epstein-Barr virus immortalized lymphocyte cell line for lysis. In vitro immunization of PBMC from HLA A*0201 and HCMV seropositive volunteers using the defined nonamer peptide stimulated significant recognition of HCMV infected or peptide-sensitized fibroblasts. Similarly, HLA A*0201 transgenic mice immunized with the nonamer peptide developed CTL that recognize both the immunizing peptide and endogenously processed pp65 in an HLA A*0201 restricted manner. Lipid modification of the amino terminus of the nonamer peptide resulted in its ability to stimulate immune respones without the use of adjuvant. This demonstration of a vaccine function of the nonamer peptide without adjuvant suggests its potential for use in an immunization trial of BMT donors to induce protective CTLs in patients undergoing allogeneic BMT.
Secondary Mutation Maintains the Transformed State in BaF3 Cells With Inducible BCR/ABL Expression
Authors: Klucher Kevin M. , Lopez David V. , Daley George Q. 
Published: October 2019

Abstract
The BCR/ABL gene product of the Philadelphia (Ph) chromosome induces chronic myelogenous leukemia (CML). We generated a hematopoietic cell line, TonB210.1, with tetracycline-dependent BCR/ABL expression to investigate the pathways by which BCR/ABL transforms cells. TonB210.1 demonstrates conditional growth factor independence in tissue culture and rapidly forms tumors in mice fed the tetracycline analog doxycycline. The tumors regress completely upon doxycycline withdrawal, but ultimately reform in all animals. After a long latency, tumors also develop in animals never exposed to doxycycline. Subclones of TonB210.1 established from doxycycline-independent tumors demonstrate distinct mechanisms of transformation. Most subclones manifest increased basal levels of BCR/ABL expression; some have lost the capacity to augment expression upon induction, whereas others remain inducible. More interestingly, some subclones maintain tight conditional expression of BCR/ABL and are therefore transformed by secondary mechanisms that no longer require BCR/ABL expression. These subclones show constitutive phosphorylation of the STAT5 protein, suggesting that activating mutations have occurred upstream in the signaling pathway to STAT5. The tight conditional expression of BCR/ABL in the TonB210.1 cell line affords the opportunity to study several interesting aspects of the biology of BCR/ABL, including activation of critical signaling pathways and transcriptional programs, and its potential role in genomic instability.
B-Cell Chronic Lymphocytic Leukemia Cells Express a Functional Inducible Nitric Oxide Synthase Displaying Anti-Apoptotic Activity
Authors: Zhao Haixia , Dugas Nathalie , Mathiot Claire , Delmer Alain , Dugas Bernard , Sigaux François , Kolb Jean-Pierre 
Published: October 2019

The expression of different isoforms of nitric oxide synthase (NOS) was investigated in B-cell chronic lymphocytic leukemia (B-CLL) to delineate a possible role for nitric oxide (NO) in the control of apoptosis of the tumoral cells. By reverse transcription-polymerase chain reaction (RT-PCR), all B-CLL cells were found to express spontaneously inducible NOS (iNOS) mRNA, whereas endothelial constitutive NOS (ecNOS) mRNA was undetectable. The iNOS protein was detected by immunofluorescence in the cytoplasm of permeabilized leukemic cells and identified by Western blotting, using different anti-iNOS antibodies, as a protein of 135 kD in B-CLL cytoplasmic extracts. B-CLL cell lysates also displayed basal NOS enzymatic activity, as measured by the conversion of14C-labeled L-arginine into 14C-L-citrulline. Ligation of CD23, expressed on the vast majority of B-CLL cells, resulted in increased iNOS expression and activity. The NO released exerted an anti-apoptotic effect on B-CLL cells that was counteracted by NOS inhibitors and engagement of the APO-1/Fas pathway. Therefore, the existence of a functional iNOS in B-CLL cells will provide further insights into the mechanisms that control proliferation and apoptosis in these tumor cells.© 1998 by The American Society of Hematology.
Release of Polymorphonuclear Leukocytes From the Bone Marrow by Interleukin-8
Authors: Terashima Takeshi , English Dean , Hogg James C. , vanEeden Stephan F. 
Published: October 2019

Several studies have shown that interleukin-8 (IL-8) causes a rapid granulocytosis with the release of polymorphonuclear leukocytes (PMN) from the bone marrow (BM) partially responsible for the granulocytosis. This study was designed to quantitate the release of PMN from the BM by IL-8 and measure the transit time of PMN through the marrow after IL-8 administration. The thymidine analogue, 5'-bromo-2'-deoxyuridine (BrdU), was used to label dividing PMN in the marrow and follow their release into the circulation after intravenous IL-8. This allowed us to calculate the transit time of PMN through the mitotic and postmitotic pools of BM. BrdU was infused intravenously into rabbits 24 hours before IL-8 (2.5 μg/kg). IL-8 caused a rapid, transient granulocytopenia (5.9 ± 0.4 at baseline v 0.2 ± 0.06 × 10/9L at 5 minutes, P < .05) followed by granulocytosis (8.4 ± 0.1 at 30 minutes, P < .05) associated with an increased number (0.3 ± 0.1 at baseline v1.2 ± 0.6 × 109/L at 30 minutes, P < .05) and percentage of band cells (P < .05), as well as a rapid increase in the number of BrdU-labeled PMN (PMNBrdU) in the circulation (0.09 ± 0.05 at baseline to 1.5 ± 0.6 × 109/L at 60 minutes, P < .05). The transit time of PMN through both the mitotic and postmitotic pools of BM was not affected by IL-8. To determine the marrow compartment from which the PMN were mobilized by IL-8, we quantitated PMN movement from the hematopoietic and sinusoidal compartments into the circulation. The fraction of PMNBrdU in both compartments was higher than in the circulating blood (P < .05) and the fraction and number of PMNBrdU in the sinusoids decreased with IL-8 treatment (P < .05). We conclude that the pool of PMN residing in the BM venous sinusoids are rapidly released into the circulation after administration of IL-8.© 1998 by The American Society of Hematology.
Role for Bcl-xL in Delayed Eosinophil Apoptosis Mediated by Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-5
Authors: Dibbert Birgit , Daigle Isabelle , Braun Doris , Schranz Corinna , Weber Martina , Blaser Kurt , Zangemeister-Wittke Uwe , Akbar Arne N. , Simon Hans-Uwe 
Published: October 2019

Eosinophils are potent inflammatory cells involved in allergic reactions. Inhibition of apoptosis of purified eosinophils by certain cytokines has been previously shown to be an important mechanism causing tissue eosinophilia. To elucidate the role of Bcl-2 family members in the inhibition of eosinophil apoptosis, we examined the expression of the known anti-apoptotic genes Bcl-2, Bcl-xL, and A1, as well as Bax and Bcl-xS, which promote apoptosis in other systems. We show herein that freshly isolated human eosinophils express significant amounts of Bcl-xL and Bax, but only little or no Bcl-2, Bcl-xS, or A1. As assessed by reverse transcription-polymerase chain reaction, immunoblotting, flow cytometry, and immunocytochemistry, we show that spontaneous eosinophil apoptosis is associated with a decrease in Bcl-xL mRNA and protein levels. In contrast, stimulation of the cells with granulocyte-macrophage colony-stimulating factor (GM-CSF) or interleukin-5 (IL-5) results in maintenance or upregulation of Bcl-xL mRNA and protein levels. Moreover, Bcl-2 protein is not induced by GM-CSF or IL-5 in purified eosinophils. Bcl-2 protein is also not expressed in tissue eosinophils as assessed by immunohistochemistry using two different eosinophilic tissue models. Furthermore, Bcl-xL antisense but not scrambled phosphorothioate oligodeoxynucleotides can partially block the cytokine-mediated rescue of apoptotic death in these cells. These data suggest that Bcl-xL acts as an anti-apoptotic molecule in eosinophils.© 1998 by The American Society of Hematology.
Intermittent, Repetitive Corticosteroid-Induced Upregulation of Platelet Levels After Adenovirus-Mediated Transfer to the Liver of a Chimeric Glucocorticoid-Responsive Promoter Controlling the Thrombopoietin cDNA
Authors: Narumi Ko , Suzuki Motoyoshi , Song Wenru , Moore Malcolm A.S. , Crystal Ronald G. 
Published: October 2019

For many in vivo gene therapy clinical applications, it is desirable to control the expression of the transferred transgene using pharmacologic agents. To evaluate the feasibility of accomplishing this using corticosteroids, pharmacologic agents widely used in clinical medicine, we constructed replication deficient adenoviral (Ad) vectors containing an expression cassette with a chimeric promoter comprised of five glucocorticoid response elements (GRE) and the chloramphenicol acetyltransferase reporter gene (AdGRE.CAT) or the murine thrombopoietin cDNA (AdGRE.mTPO). In vitro studies showed the vectors functioned as expected, with marked glucocorticoid-induced upregulation of the CAT or mTPO transgenes. To evaluate the inducibility of the GRE promoter in vivo, the AdGRE.CAT vector was administered intravenously to C57B1/6 mice, and CAT activity was quantified in liver before and after intraperitoneal administration of dexamethasone. The GRE promoter activity was dependent on the dexamethasone dose, with a 100-fold increase in CAT expression with 50 μg dexamethasone, similar to the levels observed in vivo with the Rous sarcoma virus long terminal repeat constitutive promoter. After dexamethasone administration, maximum CAT activity was observed at day 2, with a slow decline to baseline levels by 2 weeks. Based on these observations, we hypothesized that a single administration of an Ad vector-mediated transfer of the chimeric GRE inducible promoter driving the mTPO cDNA would enable repetitive administration of corticosteroids to repetitively upregulate platelet levels for 1 to 2 weeks. The data show that this occurs, with dexamethasone administration every 3 weeks associated with 1-week elevations (at each 3-week interval) of serum mTPO levels, megakaryocyte numbers in bone marrow, and platelet levels fourfold to sixfold over baseline. Thus, with the appropriate promoter, it is possible to use a commonly used pharmacologic agent to upregulate the expression of a newly transferred gene on demand.© 1998 by The American Society of Hematology.
Overexpression of HOX11 Leads to the Immortalization of Embryonic Precursors With Both Primitive and Definitive Hematopoietic Potential
Authors: Keller Gordon , Wall Charles , Fong Andrew Z.C. , Hawley Teresa S. , Hawley Robert G. 
Published: October 2019

Primitive and definitive erythropoiesis represent distinct hematopoietic programs that differ with respect to stage of development, transcriptional control, and growth regulation. Although these differences have been recognized for some time, the relationship of the two erythroid lineages to each other is not well established. We have used a model system based on the hematopoietic development of embryonic stem (ES) cells in culture to investigate the origins of the earliest hematopoietic populations. Using ES cells transduced with a retrovirus that overexpresses the HOX11 gene, we have established factor-dependent hematopoietic cell lines that represent novel stages of embryonic hematopoiesis. Analysis of three of these cell lines indicates that they differ with respect to cytokine responsiveness, cell surface markers, and developmental potential. Two of the cell lines, EBHX1 and EBHX11, display the unique capacity to generate both primitive and definitive erythroid progeny as defined by morphology and expression of βH1 and βmajor globin. The third line, EBHX14, has definitive erythroid and myeloid potential, but is unable to generate cells of the primitive erythroid lineage. Analysis of the cytokine responsiveness of the two lines with primitive erythroid potential has indicated that exposure to leukemia inhibitory factor (LIF) results in the upregulation of βH1 and a change in cellular morphology to that of primitive erythrocytes. These findings are the first demonstration of a clonal cell line with primitive and definitive hematopoietic potential and support the interpretation that these lineages may arise from a common precursor in embryonic life. In addition, they suggest that LIF could play a role in the regulation of primitive erythropoiesis.© 1998 by The American Society of Hematology.
Role of Adhesion Molecules in the Homing and Mobilization of Murine Hematopoietic Stem and Progenitor Cells
Authors: Vermeulen Monica , Le Pesteur Françoise , Gagnerault Marie-Claude , Mary Jean-Yves , Sainteny Françoise , Lepault Françoise 
Published: October 2019

Bone marrow (BM) transplantation still must overcome multiple difficulties and should benefit from better understanding of stem-cell homing and mobilization. Here, we analyzed the involvement of several adhesion molecules in the two processes by treating mice with monoclonal antibodies against these molecules. Treatment of lethally irradiated mice grafted with isogeneic BM cells showed that at least two migration pathways are important for stem-cell homing to the BM, whereas only one of them is involved in lodging of colony-forming unit–spleen (CFU-S) in the spleen. We confirm that the VLA-4/VCAM-1 adhesion pathway is important for stem-cell homing to the BM only and show that CD44 is involved in CFU-S lodging in both BM and spleen. These results show that entry of CFU-S into the spleen is regulated. The observation that when one migration pathway is altered, CFU-S do not enter the BM via the other pathway may indicate that the two mechanisms involved in CFU-S homing into the BM are linked. The adhesion molecules VLA-4 and CD44 are also implied in the mobilization of stem cells into the blood stream of mice injected once with anti–VLA-4 or anti-CD44. Anti–VLA-4 administration led to a significant increase in circulating stem cells as early as 8 hours after treatment. Stem cells mobilized by anti–VLA-4 comprise cells with high self-renewal potential and thus may be used for long-term reconstitution of the hematopoietic tissue.© 1998 by The American Society of Hematology.
Clonal Diversity of Ig and T-Cell–Receptor Gene Rearrangements Identifies a Subset of Childhood B-Precursor Acute Lymphoblastic Leukemia With Increased Risk of Relapse
Authors: Green Elaine , McConville Carmel M. , Powell Judith E. , Mann Jillian R. , Darbyshire Philip J. , Taylor A. Malcolm R. , Stankovic Tatjana 
Published: October 2019

Abstract
Current prognostic indicators such as age, sex, and white blood cell count (WBC) fail to identify all children with more aggressive forms of B-precursor acute lymphoblastic leukemia (ALL), and a proportion of patients without poor prognostic indicators still relapse. Results obtained from an analysis of 65 pediatic B-precursor ALL patients indicated that subclone formation leading to clonal diversity, as detected by Ig and T-cell receptor (TCR) gene rearrangements, may represent a very useful prognostic indicator, independent of age, sex, and WBC. Disease-free survival was significantly shorter in those patients showing clonal diversity at presentation. Furthermore, clonal diversity was detected not only in the majority of high-risk patients who relapsed but was also associated with a high probability of relapse in standard-risk patients. Sixty-five percent (13/20) of standard-risk patients who also showed clonal diversity subsequently relapsed, whereas the percentage of relapses among standard-risk patients without clonal diversity was much lower at 19% (7/36). Continued clonal evolution during disease progression is an important feature of aggressive B-precursor ALL. All 5 patients with clonal diversity who were followed up in our study showed a change in the pattern of clonality between presentation and relapse. This implies an important role for clonal diversity as a mechanism of disease progression through the process of clonal variation and clonal selection.
© 1998 by The American Society of Hematology.
Triggering of CD40 Antigen Inhibits Fludarabine-Induced Apoptosis in B Chronic Lymphocytic Leukemia Cells
Authors: Romano Maria Fiammetta , Lamberti Annalisa , Tassone Pierfrancesco , Alfinito Fiorella , Costantini Silvia , Chiurazzi Federico , Defrance Thierry , Bonelli Patrizio , Tuccillo Franca , Turco Maria Caterina , Venuta Salvatore 
Published: October 2019

We analyzed the effect of CD40 triggering on the fludarabine-induced apoptosis of B chronic lymphocytic leukemia (B-CLL) cells. Peripheral blood samples obtained from 15 patients were incubated with fludarabine in the absence or the presence of the anti-CD40 monoclonal antibody (MoAb) G28-5. In 12 patients a significant proportion of apoptotic cells, ranging from 22% to 38% (mean ± SE: 28.5 ± 1.6), were detected after 3 days of culture. In 9 of these samples, the addition of G28-5 reduced apoptosis by at least 30.1% and by 57.1% ± 7.8% on average (P = .0077). Because the CD40 antigen activates NF-κB/Rel transcription factors in B cells, and NF-κB/Rel complexes can inhibit cell apoptosis, we investigated whether the antiapoptotic effect of G28-5, in our system, could be related to modulation of NF-κB/Rel activity. As expected, B-CLL cells displayed significant levels of nuclear NF-κB/Rel activity; p50, RelA, and c-Rel components of the NF-κB/Rel protein family were identified in these complexes. After exposure to fludarabine, NF-κB/Rel complexes were decreased in the nuclei. The addition of G28-5 upregulated the NF-κB/Rel levels. To determine the involvement of NF-κB/Rel activity in the G28-5–mediated inhibition of apoptosis, we blocked the transcription factor with a decoy oligonucleotide, corresponding to the NF-κB/Rel consensus sequence. Cells incubated with the anti-CD40 MoAb in the presence of the decoy oligonucleotide but not a control oligonucleotide displayed a complete impairment of the G28-5 antiapoptotic effect, indicating that NF-κB/Rel activity was required for the inhibition of apoptosis. These results suggest that CD40 triggering in vivo could counteract the apoptotic effect of fludarabine on B-CLL cells and that its neutralization, or the use of NF-κB/Rel inhibitors, could improve the therapeutic effect of fludarabine.© 1998 by The American Society of Hematology.
Synergistic Activation of MAP Kinase (ERK1/2) by Erythropoietin and Stem Cell Factor Is Essential for Expanded Erythropoiesis
Authors: Sui Xingwei , Krantz Sanford B. , You Min , Zhao Zhizhuang 
Published: October 2019

Stem cell factor (SCF) and erythropoietin (EPO) work synergistically to support erythropoiesis, but the mechanism for this synergism is unknown. By using purified human erythroid colony-forming cells (ECFC), we have found that SCF and EPO synergistically activate MAP kinase (MAPK, ERK1/2), which correlates with the cell growth and thus may be responsible for the synergistic effects. Treatment of the cells with PD98059 and wortmannin, inhibitors of MEK and PI-3 kinase, respectively, inhibited the synergistic activation of MAPK and also the cell growth, further supporting this conclusion. Wortmannin only inhibits MAPK activation induced by EPO but not that by SCF, suggesting that SCF and EPO may activate MAPK through different pathways, which would facilitate synergy. Furthermore, EPO, but not SCF, led to activation of STAT5, whereas SCF and wortmannin had no effect on the EPO-induced STAT5 activation, suggesting that STAT5 is not involved in the synergistic action of SCF and EPO. Together, the data suggest that synergistic activation of MAPK by SCF and EPO is essential for expanded erythropoiesis.© 1998 by The American Society of Hematology.