Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023473 (chronic myeloid leukemia)
 18,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To investigate the significance of GATA-2 and immunoglobulin heavy chain germline gene C( micro ) (IgH germline gene C( micro )) expression and coexpression in various leukemia cells, GATA-2 and IgH germline gene C( micro ) mRNA in bone marrow and peripheral blood cells from 63 leukemia patients were detected by reverse transcription-polymerase chain reaction (RT-PCR). No GATA-2 or IgH germline gene C( micro ) mRNA were detected in normal bone marrow and peripheral blood. GATA-2 mRNA were be detected in 91.3% patients with acute myeloid leukemia (AML), 75% patients with acute lymphoblastic leukemia (ALL) as well as 83.3% patients with chronic myeloid leukemia (CML-CP); IgH germline gene C( micro ) mRNA were be identified in 47.8% AML, 41.6% ALL, as well as 5.6% CML-CP. All patients with CML-AP and CML-BC expressed GATA-2 mRNA and partly expressed IgH germline gene C( micro ) mRNA. 47.8% AML and 41.6% ALL patients coexpressed GATA-2 and IgH germline gene C( micro ) mRNA. GATA-2(+) IgH germline gene C( micro )(+) cells of AML and ALL were mainly HLA-DR positive. As aberration of the transcription factors, GATA-2 and germline IgH germline gene C( micro ) gene might been linked to leukemogenesis. Various expression of GATA-2 and germline IgH germline gene C( micro ) gene in leukemia might correlated with the heterogeneous differentiation level of leukemia cells. The fact that leukemia with GATA-2(+) IgH germline gene C( micro )(+) coexpression indicated multilineage impairment of hematopoietic cells.
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PMID:[Expression of GATA-2 Gene and Immunoglobulin Heavy Chain Germline Gene C( micro ) in Leukemia Cells and Its Significance] 1257 77

In a BCR/ABL-expressing myeloid precursor cell line, p53 levels were markedly downmodulated. Expression of MDM2, the negative regulator of p53, was upregulated in a tyrosine kinase-dependent manner in growth factor-independent BCR/ABL-expressing cells, and in accelerated phase and blast crisis CML samples. Increased MDM2 expression was associated with enhanced mdm2 mRNA translation, which required the interaction of the La antigen with mdm2 5' UTR. Expression of MDM2 correlated with that of La and was suppressed by La siRNAs and by a dominant negative La mutant, which also enhanced the susceptibility to drug-induced apoptosis of BCR/ABL-transformed cells. By contrast, La overexpression led to increased MDM2 levels and enhanced resistance to apoptosis. Thus, La-dependent activation of mdm2 translation might represent an important molecular mechanism involved in BCR/ABL leukemogenesis.
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PMID:BCR/ABL activates mdm2 mRNA translation via the La antigen. 1262 Apr 9

The role of BCR/ABL isoforms and their relationships to leukemia phenotype are discussed continuously because of the variety of information reported. Here we describe a man with CML an atypical b3/a3 rearrangement, who had a good response to INFalpha treatment. This may be due to a deletion of the ABL exon 2 sequences, which are an essential part of the ABL SH3 domain inducing STAT5 expression, which is indeed crucial for the BCR/ABL leukemogenesis; because of its role in anti-apoptotic activity and cell cycle progress.
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PMID:B3/A3 rearrangement in a patient with chronic myeloid leukemia. 1268 63

To obtain comprehensive information about the genes involved in BCR/ABL-dependent leukemogenesis, samples from 15 chronic myelogenous leukemia (CML) patients and seven normal donors were analysed using a cDNA microarray assay. After subtraction of the artificial, random or cross-hybridization signals, data about 5315 genes have been effectively analysed in all samples. The assay revealed >/=4-fold difference in the average expression of 263 genes in all CML samples when compared to normal counterparts, with 148 genes being upregulated and 115 being downregulated. Differentially expressed genes include those associated with BCR/ABL-induced abnormalities in signal transduction, gene transactivation, cell cycle, apoptosis, adhesion, DNA repair, differentiation, metabolism and malignant progression. Interestingly, CML-blast crisis cells in peripheral blood differ from those from bone marrow, indicating major changes in gene expression profiles upon entering into the bloodstream. Moreover, BCR/ABL modulates expression of genes, which are involved in regulation of chromosome/chromatin/DNA dynamics during S and M cell cycle phase. Moreover, the ability of CML cells to recognize and respond to a pathogen infection may be compromised. Altogether, this work provides a large body of information regarding gene expression profiles associated with CML and also represents a source of potential targets for CML therapeutics.
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PMID:Chronic myelogenous leukemia molecular signature. 1281 69

Previous studies suggested that the SH2-containing inositol-5-phosphatase (SHIP) may play a tumor suppressor-like function in BCR-ABL-mediated leukemogenesis. To investigate this possibility, we first developed a new assay for quantitating transplantable multilineage leukemia-initiating cells (L-ICs) in hematopoietic stem cell (HSC)-enriched mouse bone marrow (BM) cells transduced with a BCR-ABL-GFP (green fluorescent protein) retrovirus. The frequency of L-ICs (1 of 430 Sca-1+lin- cells) was 7-fold lower than the frequency of HSCs in the Sca-1+lin- subset transduced with a control virus (1 of 65 cells). Forced BCRABL expression was also accompanied by a loss of regular HSC activity consistent with the acquisition of an increased probability of differentiation. Interestingly, the frequency and in vivo behavior of wild-type (+/+) and SHIP-/- L-ICs were indistinguishable, and in vitro, Sca-1+lin- BCR-ABL-transduced SHIP-/- cells showed a modestly reduced factor independence. Comparison of different populations of cells from patients with chronic myeloid leukemia (CML) in chronic phase and normal human BM showed that the reduced expression of full-length SHIP proteins seen in the more mature (CD34-lin+) leukemic cells is not mirrored in the more primitive (CD34+lin-) leukemic cells. Thus, SHIP expression appears to be differently altered in the early and late stages of differentiation of BCR-ABL-transformed cells, underscoring the importance of the cellular context in which its mechanistic effects are analyzed.
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PMID:Evidence for a positive role of SHIP in the BCR-ABL-mediated transformation of primitive murine hematopoietic cells and in human chronic myeloid leukemia. 1282 95

To elucidate the role of mitogen-activated protein kinases (MAPKs) and Akt kinase in leukemogenesis caused by the breakpoint cluster region (BCR)-Abelson (ABL) tyrosine kinase oncoprotein, we examined the activities of MAPKs and Akt kinase and their roles in the action of STI571, a specific inhibitor of BCR-ABL tyrosine kinase, in chronic myelogenous leukemia (CML) cells. We found that extracellular signal-regulated kinase (ERK) 1/2 and Akt kinase are constitutively active in the chronic phase of CML, blast crisis of CML, and the CML-derived K562 cell line. Both interferon-alpha and STI571 suppressed ERK1/2 activity in K562 cells. In contrast, Akt kinase activity was inhibited only by STI571. K562 cell proliferation was markedly suppressed by LY294002, a specific inhibitor of PI3K/Akt kinase, and STI571 but not by PD98059, a specific inhibitor of MEK1/2. In addition, caspase-3 was activated by treatment of cells with STI571 and LY294002 but not with PD98059. These data indicate that Akt kinase may play a role in the proliferation of CML leukemia cells and the action of STI571. Primary leukemia cells from patients with CML blast crisis did not show inhibition of ERK1/2 or Akt kinase activity and were resistant to caspase-3-associated apoptosis after treatment with STI571. These findings suggest that STI571 does not effectively block signaling molecules downstream of the BCR-ABL tyrosine kinase in some cases of CML blast crisis.
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PMID:Involvement of Akt kinase in the action of STI571 on chronic myelogenous leukemia cells. 1285 Apr 78

The elucidation of the molecular biology of chronic myeloid leukemia (CML) has provided a paradigm for understanding leukemogenesis, targeted drug development, and disease monitoring at the molecular level. Minimal residual disease (MRD) monitoring by fluorescence in situ hybridization and polymerase chain reaction (PCR) has become an important tool in predicting relapse after allogeneic transplant, allowing for early intervention strategies such as donor lymphocyte infusion. MRD monitoring is important for assessment of disease status in patients who obtain a complete cytogenetic remission, and this approach is likely to play an important role in following patients to determine who will relapse on imatinib mesylate therapy. This review focuses primarily on MRD monitoring by PCR.
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PMID:Monitoring bcr-abl by polymerase chain reaction in the treatment of chronic myeloid leukemia. 1289 96

Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet-derived growth factor receptor, and c-kit receptor. The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR-ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR-ABL, thereby preventing tyrosine autophosphorylation, and in turn, phosphorylation of its substrates. This process ultimately results in a "switch-off" of the downstream signaling pathways that promote leukemogenesis. Despite high rates of hematologic and cytogenetic responses to imatinib therapy, the emergence of resistance to imatinib has been recognized as a major problem in the treatment of Ph-positive leukemia. Considerable progress has been made in developing therapeutic agents that are effective against molecular targets specifically expressed in CML cells. It is important to emphasize that BCR-ABL is the ideal target for therapy even at relapse; at least one general mechanism of resistance involves maintenance of an active BCR-ABL kinase inside leukemic cells. It is also notable that the high frequency of BCR-ABL mutations and amplifications represents the high degree of heterogeneity in patients with advanced CML, in whom multiple leukemic clones may exist. For these reasons, a single inhibitor is unlikely to be able to block all mutants described so far.
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PMID:[Molecular-target therapy of Ph-positive leukemia by imatinib (tyrosine kinase inhibitor)]. 1293 59

Oxysterols are oxygenated derivatives of cholesterol that have been shown to influence a wide variety of cellular processes including sterol metabolism, lipid trafficking, apoptosis and more recently, cell differentiation. The oxysterol binding proteins (OSBPs) comprise a large conserved family of proteins in eukaryotes with high affinity for oxysterols, but their precise function has not been defined yet. One member of this family in humans, HLM/OSBP2 protein, has recently been reported as a potential marker for solid tumor dissemination and worse prognosis in these cases. In this study we focused on the evaluation of HLM/OSBP2 expression in malignant cell lines from different origins (blood and solid tumors) and we also evaluated its expression in chronic myeloid leukemia patients, correlating the molecular findings with clinical outcome. Our results showed that HLM/OSBP2 was expressed in 80% of the analysed CML patients, suggesting that this protein could constitute a helpful tool for disease monitoring and reinforces recent findings that HLM/OSBP2 protein could be involved in the maintenance of the undifferentiated state necessary for leukemogenesis.
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PMID:HLM/OSBP2 is expressed in chronic myeloid leukemia. 1296 51

Chronic myeloid leukemia (CML) is a stem cell disease characterized by excessive accumulation of clonal myeloid (precursor) cells in hematopoietic tissues. CML cells display the translocation t(9; 22) that creates the bcr/abl oncogene. The respective oncoprotein (= BCR/ABL) exhibits constitutive tyrosine kinase activity and promotes growth and survival in CML cells. Clinically, CML can be divided into three phases: the chronic phase (CP), the accelerated phase (AP), and the blast phase (BP) that resembles acute leukemia. Progression to AP and BP is associated with occurrence of additional genetic defects that cooperate with bcr/abl in leukemogenesis and lead to resistance against antileukemic drugs. The prognosis in CML is variable depending on the phase of disease, age, and response to therapy. The only curative approach available to date is stem cell transplantation. For those who cannot be transplanted, the BCR/ABL tyrosine kinase inhibitor STI571 (Glivec, Imatinib), interferon-alpha (with or without ARAC), or other cytoreductive drugs are prescribed. Currently available data show that STI571 is a superior compound compared to other drugs in producing complete cytogenetic and molecular responses. However, despite superior initial data and high expectations for an effect on survival, long term results are not available so far, and resistance against STI571 has been reported. Forthcoming strategies are therefore attempting to prevent or counteract STI571 resistance by co-administration of other antileukemic drugs. Whether these strategies will lead to curative drug therapy in CML in the future remains at present unknown.
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PMID:Chronic myeloid leukemia: pathophysiology, diagnostic parameters, and current treatment concepts. 1367 68


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