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

Developing strategies to counteract imatinib resistance constitutes a challenge in chronic myelogenous leukemia (CML). Therapy with the tyrosine kinase inhibitors nilotinib (AMN107) and dasatinib (BMS-354825) has produced high rates of hematologic and cytogenetic response. Src kinase activation has been linked to Bcr-Abl-mediated leukemogenesis and CML progression. In addition to binding Abl kinase with less stringent conformational requirements than imatinib, dasatinib is a potent Src kinase inhibitor. In the current study, we report on 23 patients with CML (19 of them in accelerated or blastic phases) treated with dasatinib after treatment failure with both imatinib and nilotinib. More than half (13; 57%) of 23 patients responded to dasatinib: 10 (43%) had a complete hematologic response (CHR), including 7 (30%) who had a cytogenetic response (2 complete, 4 partial, and 1 minor). These results suggest that dasatinib may be active in some patients after failure with both imatinib and nilotinib.
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PMID:Dasatinib (BMS-354825) is active in Philadelphia chromosome-positive chronic myelogenous leukemia after imatinib and nilotinib (AMN107) therapy failure. 1699 May 91

The potent clinical responses seen in patients with chronic myeloid leukemia (CML) after administration of donor-specific lymphocytes, as well as the correlation between the presence of antigen specific T cells and prolonged remission in these patients, suggests a role for the immunological control of CML. Here we propose Aldara, a clinically used formulation of imiquimod, as an agent for augmenting immune responses to CML antigens. Our proposition is based upon 3 tenets: 1) Endogenous dendritic cells (DC) of CML patients, which are known to be derived from the malignant clone, express and present various leukemic antigens; 2) CML-antigen reactive T cell clones exist in the patient but in many situations are ineffectively stimulated to cause significant hematological responses; and 3) Antigen presentation by mature, activated DC, which endogenously express CML-antigens may endow the pre-existing ineffective T cell responses with ability to control CML progression. The practical use of Aldara as a localized activator of DC in the context of present day leukemic therapeutics, as well as various properties of this unique immune modulator will be discussed.
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PMID:Therapeutic use of Aldara in chronic myeloid leukemia. 1725 47

Chronic myelogenous leukemia (CML) is a stem cell disorder that eventually progresses to a blast crisis phase (BC) characterized by distorted apoptotic pathways. The exact mechanism leading to failure in apoptotic pathways during CML progression is unclear. In view of the central role of p53 and apaf1 in the apoptotic machinery we examined six human paired chronic and BC phases samples for their expression. Real-time PCR (RQ-PCR) experiments showed an elevation of p53 mRNA in all patients during transition to BC. However, elevation of apaf1 during BC was observed in five patients only. In contrast, one patient displayed a significant 11.5-fold reduction of apaf1 expression during the transition to BC. No apaf1 promoter methylation was observed. The reduced apaf1 expression was accompanied by a trans-dominant point mutation (H179R) in one p53 allele and the loss of the other. This mutant p53, when tested using functionality assays, was unable to activate apaf1, consequently explaining the reduced expression observed in this patient. Furthermore, the same mutant failed to activate either genes involved in apoptotic or cell cycle arrest pathways, and can be considered as a complete loss of function mutation. This specific mutation was reported in several types of cancer, but was not implicated in CML. To conclude, in this study we have demonstrated mRNA elevation of p53 and apaf1 during CML blast crisis, indicating that genes and proteins involved in cellular apoptosis might be involved in disease progression/response to therapy. Moreover, the mutated p53 discovered in the patient exhibiting lowered apaf1 expression provides, in a clinical case, the first correlation between p53 and apaf1 transcription regulation in humans.
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PMID:Apaf1 in chronic myelogenous leukemia (CML) progression: reduced Apaf1 expression is correlated with a H179R p53 mutation during clinical blast crisis. 1736 Oct 96

Deciphering the BCR-ABL-independent signaling exploited in chronic myeloid leukemia (CML) progression is an important aspect in cancer stem-cell biology. CML stem-cell compartment is dynamic as it progresses to terminal blast crisis where myeloid and lymphoid blasts fail to differentiate. We demonstrate cross-regulation of signaling network involving Sonic hedgehog (Shh), Wnt, Notch and Hox for the inexorable blastic transformation of CD34(+) CML cells. Significant upregulation in Patched1, Frizzled2, Lef1, CyclinD1, p21 (P < or =0.0002) and downregulation of HoxA10 and HoxB4 (P< or =0.0001) transcripts in CD34(+) cells distinguish blast crisis from chronic CML. We report Shh-dependent Stat3 activation orchestrates these mutually interconnected signaling pathways. Stimulation of CD34(+) CML cells with either soluble Shh or Wnt3a did not activate Akt or p44/42-mitogen activated protein kinase (MAPK) pathways. Interestingly, unlike dominant negative Stat3beta, introduction of constitutive active Stat3 in CD34(+) CML cells induces cross-regulation in gene expression. Additionally, Shh and Wnt3a-dependent regulation of cyclin-dependent kinase inhibitors (CDKI) in CML suggests their role in the network. Taken together, our findings propose that deregulation in the form of hyperactive Shh and Wnt with repressed Notch and Hox pathways involving Stat3, Gli3, beta-catenin, CyclinD1, Hes1, HoxA10 and p21 might act synergistically to form an important hub in CML progression.
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PMID:Deregulation and cross talk among Sonic hedgehog, Wnt, Hox and Notch signaling in chronic myeloid leukemia progression. 1736 Dec 18

Repetitive elements are heavily methylated in normal tissues, but hypomethylated in malignant tissues, driving the global genomic hypomethylation found in cancer. This hypomethylation results in chromosomal instability, a well-characterized feature of the advanced phases of chronic myeloid leukemia (CML). We investigated methylation changes of DNA repetitive elements (LINE1, Alu, Satellite-alpha and Satellite-2) during the progression of CML from chronic phase (CP) to blast crisis (BC). CP-CML samples were significantly more hypomethylated for all repetitive sequences compared with normal samples. Furthermore, a more profound level of hypomethylation was observed among BC samples compared with CP samples. Our data suggest that repetitive DNA hypomethylation are closely associated with CML progression.
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PMID:Repetitive DNA hypomethylation in the advanced phase of chronic myeloid leukemia. 1776 66

Chronic myeloid leukemia (CML) is a rare disease in childhood which is almost exclusively associated with bcr-abl p210 (M-bcr) rearrangements. It has been suggested that co-expression of p190 and p210 may be a pathway of CML progression in adult patients. We report two cases of pediatric patients with a diagnosis of CML who presented co-expression of the p210 and p190 transcripts during progression to the blastic phase. The present data suggest that p190 may be a secondary event in at least some cases of childhood CML, suggesting an association with progression to a blastic crisis in these patients.
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PMID:Is p190 bcr-abl rearrangement necessary for acute transformation in some p210 CML of childhood? 1849 45

Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence in leukemic stem cells of the Philadelphia chromosome (Ph) and the formation of the BCR-ABL1 fusion. Untreated, the disease progresses to accelerate phase and blast crisis in which hematopoietic differentiation has become arrested. CML progression is frequently associated with cytogenetic evidence of clonal evolution, defined as additional chromosomal aberrations. We here report a CML resistant to tyrosine kinase inhibitors that rapidly progressed to blastic phase. At this time, array CGH performed on CD34(+) cells revealed cryptic partial deletions of both PRDM16 and RUNX1 and duplication of the der(21) chromosome. These genomic rearrangements were confirmed by FISH with probes targeting the deletion on chromosome 21 (24 kb), and with BAC probes flanking the deletion on 1p36 (220 kb). However, no cryptic t(1;21)(p36;q22) and/or RUNX1-PRDM16 were detected, suggesting that these deletions are the residual hallmarks of a more complex mechanism of chromosomal rearrangement, as indicated by the additional inversion of the region bounded by 1p36.32 and 1p36.12 breaks. At the molecular level, these abnormalities lead to the overexpression of the PR-domain negative oncogenic isoform of PRDM16, associated with two deleted copies within the runt domain of C-teminal aberrant RUNX1. These events are not detectable by conventional cytogenetic and molecular strategies, and may be of underestimated frequency in disease progression.
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PMID:Cryptic and partial deletions of PRDM16 and RUNX1 without t(1;21)(p36;q22) and/or RUNX1-PRDM16 fusion in a case of progressive chronic myeloid leukemia: a complex chromosomal rearrangement of underestimated frequency in disease progression? 1876 45

Chronic myeloid leukemia (CML) has been regarded as the paradigmatic example of a malignancy defined by a unique molecular event, the BCR-ABL1 oncogene. Decades of research zeroing in on the role of BCR-ABL1 kinase in the pathogenesis of CML have culminated in the development of highly efficacious therapeutics that, like imatinib mesylate, target the oncogenic kinase activity of BCR-ABL1. In recent years, most research efforts in CML have been devoted to developing novel tyrosine kinase inhibitors (TKIs) as well as to elucidating the mechanisms of resistance to imatinib and other TKIs. Nonetheless, primordial aspects of the pathogenesis of CML, such as the mechanisms responsible for the transition from chronic phase to blast crisis, the causes of genomic instability and faulty DNA repair, the phenomenon of stem cell quiescence, the role of tumor suppressors in TKI resistance and CML progression, or the cross-talk between BCR-ABL1 and other oncogenic signaling pathways, still remain poorly understood. Herein, we synthesize the most relevant and current knowledge on such areas of the pathogenesis of CML.
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PMID:Molecular biology of bcr-abl1-positive chronic myeloid leukemia. 1882 85

Signaling initiated by the BCR-ABL1 kinase causes chronic myelogenous leukemia (CML). Recently, we reported that expression of Fyn, a Src kinase, is heightened in CML cells and patient specimens and confers in vitro and in vivo proliferative advantages. Fyn is regulated by redox, and because BCR-ABL1 raises intracellular oxidant levels, which have been implicated in CML progression, we explored the molecular regulation of Fyn. Here we identify the transcription factors that drive redox- and BCR-ABL1-dependent Fyn expression. Promoter deletion analysis in 293T, BaF3, BaF3-p210, and K562 cells identified the region essential for basal transcriptional activity. Mutation of Sp1 and Egr1 binding sites within the essential region diminished Fyn promoter activity and identified Egr1 as conferring redox sensitivity. Gel shift and chromatin immunoprecipitation assays confirmed the binding of Sp1 and Egr1 to the promoter fragments. Importantly, knockdown of Sp1 or Egr1 with small interference RNA or inhibition of Sp1 binding by mithramycin A repressed Fyn protein expression. Our work is the first to define transcription factors that are responsible for endogenous, oxidative stress-dependent and BCR-ABL1-dependent Fyn expression.
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PMID:Oxidative stress promotes transcriptional up-regulation of Fyn in BCR-ABL1-expressing cells. 1913 39

Chronic myeloid leukemia (CML) progression is characterized by occurrence of new cytogenetic and molecular abnormalities. In the previous study, we have shown the important role of GATA-2 L359 V mutation in CML progression. To further ascertain the truth of transcription factor GATA-2 in hematological malignancies, we expanded our study to GATA-2 full length by directly sequencing and applied MassARRAY assay into GATA-2 L359 V mutation analysis. Finally, no GATA-2 L359 V mutation was found in 270 acute myeloid leukemia, 30 myelodysplastic syndrome, 50 acute lymphoblastic leukemia, 12 chronic lymphocytic leukemia, 40 CML chronic phase and 286 BCR/ABL negative myeloproliferative disorders except CML blast crisis. A new variation of GATA-2 resulted in P250A change was identified, which was not found to have statistical difference between patients with hematological malignancies and healthy control. Hence, we concluded GATA-2 L359 V is exclusively associated with CML progression but not other hematological malignancies and P250A is a new single nucleotide polymorphism.
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PMID:GATA-2 L359 V mutation is exclusively associated with CML progression but not other hematological malignancies and GATA-2 P250A is a novel single nucleotide polymorphism. 1930 23


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