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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The influence of bcl-2 activity on 2'-deoxyadenosine-induced apoptosis was investigated in 697 human pre-B leukemia cells stably transfected with expression plasmid pHeBo-BCL-2alpha (697/BCL2 cells). Apoptosis was induced by the 2'-deoxyadenosine analogue, 2-chloro-2'-deoxyadenosine (Cl-dA), with the concentration for apoptosis in one-half of the cells at 24 hours (LD(50)) being 10 microM for 697 cells and 120 microM for 697/Bcl 2 cells. There was a strong positive correlation between Cl-dATP levels and apoptotic index (coefficient of determination, r(2)=0.95; P=0.027). When 697 cell and 697/Bcl 2 cell lines were treated with 5 microM Cl-dA, Cl-dATP did not significantly accumulate in the latter. The Cl-dATP/dATP ratio was 0.03 in Cl-dA treated 697/Bcl 2 cells but nearly 6 in treated 697 cells. Bcl 2 overproduction also suppressed the accumulation of dAMP, dADP and dATP in cells exposed to 2'-deoxyadenosine in the presence of pentostatin to abrogate the pronounced inversion of ATP/dATP pools associated with 2'-deoxyadenosine exposure. These results suggest that one consequence of bcl-2 activity is suppression of 2'-deoxyadenosine phosphorylation and elevation in the apoptotic target cells. Relief from deoxyadenylate stress imbalances implies a novel upstream site of bcl-2 activity.
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PMID:Bcl-2 relieves deoxyadenylate stress and suppresses apoptosis in pre-B leukemia cells. 1718 17

Male contraception has focused, to a great extent, on approaches that induce azoospermia or severe oligospermia through accelerated germ cell apoptosis. Understanding the specific steps in the germ cell apoptotic pathways that are affected by male contraceptives will allow more specific targeting in future contraceptive development. In this study, we have used a nonhuman primate model to characterize the key apoptotic pathway(s) in germ cell death after mild testicular hyperthermia, hormonal deprivation, or combined interventions. Groups of 8 adult (7- to 10-year-old) cynomolgus monkeys (Macaca fascicularis) received one of the following treatments: 1) two empty silastic implants; 2) two 5.5-cm testosterone (T) implants; 3) daily exposure of testes to heat (43 degrees C for 30 min) for 2 consecutive days; and 4) two T implants plus testicular heat exposure for two consecutive days. Testicular biopsies were performed before and at Days 3, 8, and 28 of treatment. Treatment with T, heat, or both led to sustained activation of both mitogen-activated protein kinase (MAPK) 1/3 and MAPK14. Activation of MAPK1/3 and MAPK14 were accompanied by an increase in B-cell leukemia/lymphoma (BCL) 2 levels in both cytosolic and mitochondrial fractions of testicular lysates (BAX levels remained unaffected) and cytochrome c and DIABLO release from mitochondria. These treatments also resulted in inactivation of BCL2 through phosphorylation at serine 70, thereby favoring the death pathway. We conclude that the serine phosphorylation of BCL2 and activation of the MAPK14-mediated mitochondria-dependent pathway are critical for male germ cell death in monkeys.
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PMID:Signaling pathways for germ cell death in adult cynomolgus monkeys (Macaca fascicularis) induced by mild testicular hyperthermia and exogenous testosterone treatment. 1737 39

Apoptotic cell death is a highly regulated process, which plays a crucial role in many biological events. Etoposide is an antineoplastic drug, which targets the DNA unwinding enzyme, topoisomerase II. The aim of the present research approach to investigate the expression of the apoptosis-related genes BCL2 (Bcl-2), FAS, Caspase-3, BAX and the new member BCL2L12, cloned by our group, along with treatment of HL-60 leukemia cells with etoposide. The kinetics of apoptosis induction and cell toxicity was evaluated by DNA laddering and MTT method, respectively. The mRNA expression levels of the genes were analyzed by RT-PCR using gene-specific primers. Beta-actin was used as a control gene. An important downregulation of BCL2L12 was observed at 4 h of drug treatment, whereas BAX was upregulated at the same time point. No alteration in the expression pattern of the other apoptosis-related genes was detected. Since, the main anticarcinogenic effect of etoposide is due to the induction of apoptosis, these changes observed in the mRNA expression levels of the genes may be an underlying mechanism.
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PMID:Alterations in mRNA expression of apoptosis-related genes BCL2, BAX, FAS, caspase-3, and the novel member BCL2L12 after treatment of human leukemic cell line HL60 with the antineoplastic agent etoposide. 1738 50

Follicular lymphoma (FL) is a neoplasm originating from germinal centre cells, corresponding to 25-40% of non-Hodgkin's lymphomas. Transformation into diffuse large B cell lymphoma (DLBCL) occurs in about one-third of cases. CD5 is expressed in B-chronic lymphoid leukaemia/small lymphocytic lymphoma and mantle cell lymphoma, but can rarely be expressed in conjunction with CD10 in well-documented cases of FL. In this report one case of grade 1 FL is described, which transformed into a DLBCL 6 months after initial diagnosis, with both tumours expressing CD5. In both specimens, neoplastic cells were strongly positive for CD20, CD79a, bcl-2, bcl-6 and CD5 in virtually all cells. CD10 was strongly positive in initial specimens and weakly positive in the DLBCL. Investigation using the PCR confirmed the derivation of the DLBCL from the FL as they presented the same immunoglobulin heavy chain gene rearrangement and the same BCL2-J(H) break point.
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PMID:CD5-positive diffuse large B cell lymphoma arising from a CD5-positive follicular lymphoma. 1751 19

In addition to its loss playing a pivotal role in the development of a childhood kidney malignancy, the Wilms tumour 1 gene (WT1) has emerged as an important factor in normal and malignant haematopoiesis. Preferentially expressed in CD34+ haematopoietic progenitors and down-regulated in more-differentiated cells, the WT1 transcription factor has been implicated in regulation of apoptosis, proliferation and differentiation. Putative target genes, such as BCL2, MYC, A1 and cyclin E, may cooperate with WT1 to modulate cell growth. However, the effects of WT1 on target gene expression appear to be isoform-specific. Certain WT1 isoforms are over-represented in leukaemia, but the exact mechanisms underlying the role of WT1 in transformation remain unclear. The ubiquity of WT1 in haematological malignancies has led to efforts to exploit it as a marker for minimal residual disease and as a prognostic factor, with conflicting results. In vitro killing of tumour cells by WT1-specific CD8+ cytotoxic T lymphocytes facilitated design of Phase I vaccine trials that showed clinical regression of WT1-positive tumours. Alternative methods employing WT1-specific immunotherapy are being investigated and might ultimately be used to optimise multimodal therapy of haematological malignancies.
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PMID:The role of the Wilms tumour gene (WT1) in normal and malignant haematopoiesis. 1752 67

FLT3 defines a promising target for the treatment of acute myeloid leukemia (AML). In contrast to their efficacy in cell lines, FLT3-specific inhibitors as single agents have only modest clinical activity in patients with AML. As demonstrated here, overexpression of anti-apoptotic proteins of the BCL2 family leads to resistance against FLT3 inhibitors in a hematopoietic cell line model with activating FLT3 mutations. The susceptibility to FLT3 inhibition could be restored by treatment with the novel BH3 mimetic ABT-737. Primary AML samples tested in our study showed a high expression of BCL2 protein, but not of BCL-xL or MCL1. BCL2 protein levels were not reduced after dephosphorylation of FLT3 and its downstream target STAT5 in patient samples with FLT3 internal tandem duplications. Interestingly, treatment with ABT-737 caused apoptotic cell death in all primary AML samples at submicromolar level and synergized efficiently with FLT3 inhibition in AML samples with activating FLT3 mutations. In contrast to AML cell lines, BCR-ABL transformed human cells showed resistance to ABT-737, which might be due to the induction of MCL1 by BCR-ABL. Inhibition of BCL2 family members might define a novel highly efficient and specific strategy in the combined or monotreatment of AML.
Leukemia 2007 Aug
PMID:BH3 mimetic ABT-737 neutralizes resistance to FLT3 inhibitor treatment mediated by FLT3-independent expression of BCL2 in primary AML blasts. 1755 84

Array-based comparative genomic hybridization (array CGH) enables us to detect the genomic copy number alterations of cancers with high resolution. Our established array CGH platform consists of 2,304 BAC/PAC clones covering the whole genome at 1.3-mega base resolutions. Using this technique, we were thus able to reveal disease-specific genomic alterations and the candidate target genes in various lymphomas. We herein report the characteristic genomic alterations of malignant lymphomas including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and adult T cell lymphoma/leukemia (ATLL). The combined use of the array CGH data with gene expression profiling and specific gene rearrangement analyses further delineated the subtype-specific genomic alterations. For instance, we revealed that activated B-cell-like DLBCL is characterized by a gain of chromosome 3, 18q and loss of 9 p21, whereas the germinal center B-cell-like DLBCL is characterized by a gain of 2p15, 7q, and 12q. Among these genomic alterations,we found the 9 p21 loss (p16INK4a locus) to be the most aggressive type of DLBCL. Comparisons of the genome profiles of FL,both with and without BCL2 rearrangement, also revealed the existence of a unique subgroup: trisomy 3 FL. Comparison of genome profiles between acute type and lymphoma types of adult T cell lymphoma also demonstrated that acute and lymphoma types are genomically distinct subtypes, and thus may develop tumors via distinct genetic pathways. In addition to identifying disease-specific genomic alterations, we also discovered several target genes of the genomic gains and losses. Furthermore,we developed a computer algorithm to classify lymphoma diseases or subtypes on the basis of copy number gains and losses. We applied the algorithm to the classifications of DLBCL and MCL diseases and ABC and GCB subtypes. The method correctly classified the DLBCL and MCL diseases at 89%, and ABC and GCB subtypes at 83%. These results demonstrate that copy number gains and losses detected by array CGH could be used for classifying lymphomas into biologically and clinically distinct diseases or subtypes. The genomic copy number alterations detected by array CGH are therefore considered to have the potential to help diagnose or classify different disease entities and tumor subtypes.
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PMID:[Analysis of genomic copy number alterations of malignant lymphomas and its application for diagnosis]. 1763 30

Recently, a new member of the human SR (Ser/Arg-rich) superfamily of pre-mRNA splicing factors, SRA1 (SR-A1), has been discovered and cloned by members of our group, the gene for which was found to be overexpessed in a series of human tumors. In the present study, we investigated the significance of alterations at the mRNA expression levels of the SRA1 gene after treatment of HL-60 human promyelocytic leukemia cells with the anticancer drugs cisplatin and bleomycin. The kinetics of apoptosis and cell toxicity were investigated by DNA laddering and the MTT and trypan blue assays, respectively. Total RNA was extracted and cDNA was prepared by reverse transcription. The splicing-related genes SRA1 and SC35, as well as the apoptosis-related gene BCL2 (Bcl-2), were amplified by PCR using gene-specific primers. The results showed that mRNA levels of SRA1 were up-regulated upon treatment with the antibiotic bleomycin, whereas they were down-regulated by treatment of HL-60 human promyelocytic leukemia cells with cisplatin. Our results support the hypothesis that mRNA expression analysis of SRA1 may serve as a new prospective molecular marker, playing an important role in chemotherapy outcome in human leukemia.
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PMID:Effect of bleomycin and cisplatin on the expression profile of SRA1, a novel member of pre-mRNA splicing factors, in HL-60 human promyelocytic leukemia cells. 1765 95

Constitutional trisomy 8 mosaicism (CT8M) has been considered to be the first mutation in multistep carcinogenesis. We describe the case of a 38-year-old woman with a normal phenotype who developed to acute monocytic leukemia with a novel t(8;18)(q13;q21). Chromosome analysis and spectral karyotyping showed 47,XX,+8,t(8;18)(q13;q21)[20]. Fluorescence in situ hybridization (FISH) demonstrated that the breakpoint at 18q21 was centromeric to the MALT1 and BCL2 genes. FISH also revealed that trisomy 8 was detected in buccal mucosa cells, indicating that trisomy 8 was a constitutional abnormality. These results suggest that t(8;18)(q13;q21) had a crucial role in the development of leukemia as the second mutation following CT8M.
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PMID:A novel t(8;18)(q13;q21) in acute monocytic leukemia evolving from constitutional trisomy 8 mosaicism. 1765 58

Glucocorticoid (GC)-induced apoptosis is essential in the treatment of acute lymphoblastic leukemia (ALL) and related malignancies. Pro- and anti-apoptotic members of the BCL2 family control many forms of apoptotic cell death, but the extent to which this survival 'rheostat' is involved in the beneficial effects of GC therapy is not understood. We performed systematic analyses of expression, GC regulation and function of BCL2 molecules in primary ALL lymphoblasts and a corresponding in vitro model. Affymetrix-based expression profiling revealed that the response included regulations of pro-apoptotic and, surprisingly, anti-apoptotic BCL2 family members, and varied among patients, but was dominated by induction of the BH3-only molecules BMF and BCL2L11/Bim and repression of PMAIP1/Noxa. Conditional lentiviral gene overexpression and knock-down by RNA interference in the CCRF-CEM model revealed that induction of Bim, and to a lesser extent that of BMF, was required and sufficient for apoptosis. Although anti-apoptotic BCL2 members were not regulated consistently by GC in the various systems, their overexpression delayed, whereas their knock-down accelerated, GC-induced cell death. Thus, the combined clinical and experimental data suggest that GCs induce both pro- and anti-apoptotic BCL2 family member-dependent pathways, with the outcome depending on cellular context and additional signals feeding into the BCL2 rheostat.
Leukemia 2008 Feb
PMID:The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. 1804 49


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