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)

Chronic myeloid leukemia(CML) is a generic term that includes five subtypes; i.e. chronic granulocytic leukemia(CGL) (95% of all CML, 90% are Ph+, 5% are Ph-, BCR/ABL+), atypical CML(survival is worse than that of CGL), chronic myelomonocytic leukemia(a subtype of myelodysplastic syndrome), chronic neutrophilic leukemia (Ph-, BCR/ABL-) and juvenile CML(Ph-, BCR/ABL-). It is not so easy to make a diagnosis of Ph-negative CML. Also, about 25% of adult acute lymphoid leukemia(ALL) patients and some essential thrombocythemia patients have Ph chromosome. In addition, about a half of cases with Ph-positive ALL have the same size of BCR/ABL fusion protein as that in Ph-positive CML. It is necessary to distinguish them by the distinctive morphological, cytogenetical and immunological characteristics of these diseases.
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PMID:[Differential diagnosis of chronic myeloid leukemia and the related disorders]. 1176 39

Chronic myelogenous leukemia (CML) with a minor bcr-abl transcript is a rare entity. We describe a 66-year-old female who was diagnosed with CML in the chronic phase. Molecular analysis of her Philadelphia chromosome using the reverse transcriptase polymerase chain reaction and subsequent sequencing revealed a minor bcr-abl transcript. Monocytosis resembling chronic myelomonocytic leukemia was observed without splenomegaly and basophilia. Her clinical course was indolent and maintained the chronic phase of CML for nearly 3 years under hydroxyurea treatment. A review of the 23 cases of m-bcr CML including this case showed the presence of monocytosis and the absence of basophilia and splenomegaly in 55.0%, 55.0%, and 70.0% of patients, respectively. The absence of basophilia was a significant finding in patients without monocytosis ( P=0.01). Although the hematological features or clinical outcomes were variable in m-bcr CML cases, all three cases at the onset of the blastic phase showed lymphoid crisis, implying an increased lymphoid leukemogenicity of minor bcr-abl transcripts.
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PMID:Lymphoid preponderance and the absence of basophilia and splenomegaly are frequent in m-bcr-positive chronic myelogenous leukemia. 1197 25

Clonal expansion of leukemic cells is thought to be due to proliferation in excess of apoptosis. To define and compare proliferation and apoptosis between various leukemias and myelodysplastic syndrome (MDS), we measured proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine (BrdU) incorporation as surrogate markers for proliferation and caspase 3 activity and annexin V surface binding as surrogate markers for activation of the apoptotic cascade in patients with MDS, chronic myelomonocytic leukemia (CMML), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and chronic myeloid leukemia (CML). We found high proliferation in bone marrow cells from MDS and CMML as measured by PCNA and BrdU incorporation. The lowest level of proliferation was found in CLL. Apoptosis was also highest in MDS and CMML as measured by annexin V and caspase 3 activity. Unexpectedly, we found no significant difference in proliferation in bone marrow CD34+ cells from various leukemias or MDS. Apoptosis was significantly higher in bone marrow CD34+ cells from MDS and CML in chronic phase as compared to CD34+ cells from AML patients. Our results illustrate differences in proliferation and apoptosis between acute and chronic leukemias and MDS. These differences may have diagnostic and therapeutic implications.
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PMID:Proliferation and apoptosis in acute and chronic leukemias and myelodysplastic syndrome. 1200 3

The manifestations, diagnosis and management of the rarer chronic myeloid leukemias are reviewed, with special attention to problems that affect elderly patients. The spectrum of disorders includes atypical myeloproliferative syndrome, so-called Ph-negative CGL, chronic myelomonocytic leukemia, and leukemias characterized by chronic proliferation of neutrophil, eosinophil, or basophil leukocytes. These latter are sometimes difficult to differentiate from chronic nonleukemic proliferations of the index cells. Termination in an acute myeloid leukaemia that is usually refractory to treatment may occur in any of the above disorders but is not a constant event.
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PMID:Management of the chronic leukemias: special considerations in the elderly patient. Part III rarer chronic myeloid leukemias. 1217 71

In previous studies, we demonstrated that the diphtheria toxin-urokinase fusion protein DTAT was selectively toxic to acute myeloid leukemia (AML) cell lines overexpressing the CD87 urokinase receptor. In the present study, we analyzed the sensitivity of patient leukemic progenitors to DTAT and correlated the sensitivity with CD87 expression. We isolated leukemic blasts by density gradient centrifugation and performed immunophenotyping by flow cytometry and blast sensitivity measurements by inhibition of cell proliferation and colony formation in semisolid media. We found CD87 overexpression in 18 (25%) of 71 patient leukemic blast samples, including 18 (28%) of 64 myeloid malignancies and 0 (0%) of 7 lymphoid malignancies. DTAT was toxic to patient leukemic blasts by both proliferation inhibition (IC50 <or=1 nM DTAT in 18/69 evaluable samples) and colony formation inhibition (>85% inhibition by 10 nM DTAT in 11/41 evaluable samples). Only AML and chronic myeloid leukemia (CML) blast crisis blasts (18/61 [30%]) were sensitive to DTAT by the proliferation inhibition assay. Lymphoid leukemia and chronic phase CML/chronic myelomonocytic leukemia (CMML) progenitors were insensitive to DTAT by the proliferation inhibition assay (n = 7 and n = 3, respectively). Similarly, normal marrow progenitors were insensitive to DTAT by both proliferation inhibition (n = 2) and colony inhibition (n = 5) assays. The DTAT toxicity measured by both proliferation inhibition assay and colony inhibition assay correlated with CD87 density (p < 0.0001 and p = 0.001, respectively). DTAT toxicity results were similar for leukemic blasts measured by either of the two assays (p = 0.0002). This study provides the first evidence that a urokinase receptor targeted diphtheria fusion protein is toxic to patient AML blasts. The work also suggests that blast proliferation assays yield similar responses to leukemia colony-forming cell colony assays.
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PMID:Malignant progenitors from patients with CD87+ acute myelogenous leukemia are sensitive to a diphtheria toxin-urokinase fusion protein. 1242 85

Significant advances have occurred in understanding the molecular pathogenesis of human leukemias. Analysis of patient karyotypes reveals that nonrandom, somatically acquired translocations and inversions occur in most acute myeloid leukemias. Among these, fusion oncogenes have been identified that utilize similar signal transduction pathways and transcriptional activation pathways to mediate their leukemogeneic effect. In chronic myeloid leukemia (CML), both in vitro and in vivo animal studies show that BCR-AB expression leads to clinical manifestations of CML, demonstrating that BCR-AB and its fusion proteins are central mediators of myeloid proliferation and transformation in these malignancies. In other CML syndromes (chronic myelomonocytic leukemia, atypical CML), cloning of chromosomal translocation breakpoints has identified a spectrum of constitutively activated tyrosine kinases. These tyrosine kinase fusions alone apparently are both necessary and sufficient to recapitulate the disease phenotype in the murine model. In contrast, acute myelogenous leukemia (AML) is typified by chromosomal translocations involving transcription factors needed for normal myeloid differentiation. The functional consequence of translocations is loss of function of these transcription factors, resulting in impaired myeloid differentiation. However, these alone are not sufficient to cause acute leukemia; evidence strongly supports the hypothesis that second mutations are required. Data suggest a multistep pathogenesis for AML in which class I mutations, such as activating point mutations in receptor tyrosine kinases (eg, FLT3 and c-KIT), provide a proliferative and/or survival signal to hematopoietic progenitors. Class II mutations are those targeting hematopoietic transcription factors and serving primarily to impair differentiation and subsequent apoptosis. Together, these mutations result in leukemic cells capable of proliferation and survival but not differentiation. The clinical and therapeutic implication is that it may be possible to target both classes of mutations using selected or screened small-molecule inhibitors. Insights gained from molecular genetic analysis of AML provide the basis for a rational, targeted therapeutic approach.
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PMID:Molecular genetics of human leukemias: new insights into therapy. 1244 46

We describe a case of Philadelphia chromosome-positive chronic myeloid leukemia (Ph-positive CML) expressing p190(BCR-ABL). Reverse transcription-polymerase chain reaction (RT-PCR) analysis of bone marrow cells showed a 472-bp band using primers specific for the p190(BCR-ABL) but not p210(BCR-ABL) transcript. Sequencing analysis revealed that the PCR product was derived from the fusion between BCR exon e1 and ABL exon a2 (e1a2). CML expressing p190(BCR-ABL) is relatively rare. In a review of the literature, it may be grouped into 2 categories; approximately half of the patients exhibited prominent monocytosis and intermediate hematological phenotype between CML and chronic myelomonocytic leukemia, and the remaining patients showed no monocytosis.
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PMID:Philadelphia chromosome-positive chronic myeloid leukemia expressing p190(BCR-ABL). 1252 Nov 92

Deregulation of protein kinase activity has been shown to play a central role in the pathogenesis of human cancer. The molecular pathogenesis of chronic myelogenous leukemia (CML) in particular, depends on formation of the bcr-abl oncogene, leading to constitutive expression of the tyrosine kinase fusion protein, Bcr-Abl. Based on these observations, imatinib was developed as a specific inhibitor for the Bcr-Abl protein tyrosine kinase. The expanding understanding of the basis of imatinib-mediated tyrosine kinase inhibition has revealed a spectrum of potential new antitumor applications beyond the powerful activity already reported in the treatment of CML. Imatinib has shown activity in vivo against PDGF-driven tumor models including glioblastoma, dermatofibrosarcoma protuberans and chronic myelomonocytic leukemia. Antiangiogenic effects have been demonstrated by inhibition of PDGF-, VEGF (vascular endothelial growth factor)- and bFGF- (basic fibroblast growth factor) induced angiogenesis in vivo, and by inhibition of angiogenesis and tumor growth in an experimental bone metastasis model. Imatinib has been shown to reduce interstitial fluid pressure in an experimental colonic carcinoma model by blocking PDGF-mediated effects on tumor-associated blood vessels and stromal tissue. It is also a potent inhibitor of the Kit receptor tyrosine kinase, and has demonstrated activity clinically against the Kit-driven gastrointestinal stromal tumor (GIST) and experimentally in small-cell lung cancer cell lines. The pharmacology of imatinib and its activity in various tumor models is discussed.
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PMID:Pharmacology of imatinib (STI571). 1252 70

The platelet-derived growth factors (PDGF) are a pleotrophic family of peptide growth factors that signal through cell surface, tyrosine kinase receptors (PDGFR) and stimulate various cellular functions including growth, proliferation, and differentiation. To date, PDGF expression has been demonstrated in a number of different solid tumors, from glioblastomas to prostate carcinomas. In these various tumor types, the biologic role of PDGF signaling can vary from autocrine stimulation of cancer cell growth to subtler paracrine interactions involving adjacent stroma and vasculature. The tyrosine kinase inhibitor imatinib mesylate (formerly STI571, Gleevec, Novartis Pharmaceuticals Corp, East Hanover, NJ) blocks activity of the Bcr-Abl oncoprotein and the cell surface tyrosine kinase receptor c-Kit, and as such was recently approved for several indications in the treatment on chronic myeloid leukemia and gastrointestinal stromal tumors. In both of these examples the target protein was identified by an oncogenic, activating mutation. Imatinib mesylate is also a potent inhibitor of PDGFR kinase and is currently being evaluated for the treatment of chronic myelomonocytic leukemia and glioblastoma multiforme, based upon evidence in these diseases of activating mutations in PDGFR. However, the PDGF pathway may represent a therapeutic target in other solid tumors in which it is not part of the oncogenic transformation. In order to investigate the potential biologic implications of inhibiting PDGFR in these tumor types, clinical trials that investigate both established clinical endpoints of response and benefit, as well as surrogate endpoints that describe the biologic significance of PDGF inhibition in vivo are needed.
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PMID:Targeting PDGF receptors in cancer--rationales and proof of concept clinical trials. 1290 55

Present study consists of cytogenetic evaluation in 141 cases referred to our centre for various leukemias. This includes 110 cases of CML, 10 of ALL, 16 of AML (M3), 2 of AML(M2), 2 of MDS and 1 of CMML. The conventional cytogenetic study was carried out in all the cases using G Banding technique. Of the 141 patients studied, 17 patients showed secondary chromosomal alterations along with primary chromosomal alterations. In two patients of CML with secondary chromosomal alteration t(4:9:22), molecular cytogenetic technique (FISH) has been carried out which has confirmed the primary observations revealed by the conventional cytogenetic technique. Other secondary alterations were numerous and would have been missed if only FISH or PCR technique would have been used for diagnosis. We observed from our study that advanced molecular techniques like FISH and PCR cannot replace the conventional cytogenetic study but are useful as supportive and confirmative diagnostic tools.
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PMID:Usefulness of cytogenetics in leukemias. 1292 72


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