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)

The translocation t(3;21)(q26;q22) is a rare recurring clonal abnormality, either preceding or associated with blast crisis in Philadelphia chromosome-positive chronic myeloid leukemia (CML) patients. We previously localized the chromosomal breakpoints at 3q26.2 and 21q22.2, using high resolution chromosomal analysis. Two genes of interest are localized near the breakpoints, the transferrin receptor gene and the ETS2 proto-oncogene. Their chromosomal localizations, determined by in situ hybridization on normal metaphase cells, were 3q29 and 21q22.3, respectively. They underwent a reciprocal translocation in patients with t(3;21). Their structures were not altered by the translocation, and both were expressed to varying levels in t(3;21) patients. Southern blotting investigations showed that the structure of other single-copy genes, including FIM3, localized near the breakpoints, were not affected by the translocation. An analysis of ETS2 expression performed on CML patients without t(3;21) showed the presence of the transcript in 100% of the blast crises, but only in 20% of the chronic-phase patients. Thus ETS2 expression may either be linked to or play a role in CML progression.
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PMID:Expression of the ETS2 and transferrin receptor genes in Philadelphia-positive chronic myeloid leukemia patients with a reciprocal t(3;21). 138 56

The expression of C-myc proto-oncogene were studied at the levels of protein in bone marrow cells obtained from patients with AML and CML. It was found that the expression of C-myc in florid AML and during blast phase of CML were much higher than that in remission of AML and in chronic phase of CML. In 7 cases of AML diagnosed for the first time, 2 cases with high C-myc expression had no remission after 3-6 months, while 5 with rare C-myc expression had remission after 3-6 months. This results suggest that the expression of C-myc proto-oncogene are possibly sensitive indicator of the prognosis of leukemia.
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PMID:[The expression of C-myc oncogene in leukemia and its relationship to clinical symptoms]. 139 24

DNA methylation plays an important role in gene regulation. We have analyzed the methylation status of CCGG sites in and around the human proto-oncogene c-myc in blood cells from patients with acute and chronic leukemias and with myelodysplastic syndromes using restriction endonucleases. The 5' region of c-myc was unequivocally hypomethylated in all the 58 specimens studied, including 10 from normal bone marrow and 1 from human placenta. In contrast, the 3' region was hypermethylated in a great majority of cases. However, this region was hypomethylated in 1 of 12 patients with de novo acute myeloid leukemia, 1 of 6 patients with chronic myeloid leukemia, and 4 of 5 patients with acute myeloid leukemia preceded by a documented stage of myelodysplastic syndromes. One possible mechanism for the 3' region of c-myc to have remained hypomethylated may be a "delayed methylation" during transforming events toward a more aggressive stage of the disease, but the precise mechanism is unknown.
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PMID:Methylation status of c-myc oncogene in leukemic cells: hypomethylation in acute leukemia derived from myelodysplastic syndromes. 146 40

Leukemias are characterized by an idiopathic proliferation of a progenitor cell that is committed to a single cell lineage. However, leukemias with dual-lineage differentiation are being described, especially within the pediatric age group. The authors reviewed 118 cases of adult acute leukemia phenotyped by immunofluorescent flow cytometry; 7 cases demonstrated mixed cell lineage. Immunophenotypically these cases were defined by early B-lymphocyte differentiation (TdT, HLA-DR, and CD19) coexpressed with a myeloid receptor (CD13, CD15, or CD33) on the same leukemic cell. Routine cytochemical evaluation demonstrated punctate positivity of the blasts with naphthol AS-D chloroacetate esterase stain in five of seven cases. Cytogenetic analysis revealed structural abnormalities of chromosome 11 in four of the seven cases. Three of these studies showed a break at 11q23-24, the location of the human proto-oncogene ets-1. Clinically, two of these leukemias represented chronic myelogenous leukemia in blast crisis, and all cases behaved aggressively. The authors' data suggest that mixed lineage leukemias are an identifiable subset of adult acute leukemias and are associated with a poor prognosis.
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PMID:Biphenotypic acute leukemia in adults. 169 92

Chronic myelogenous leukemia and one type of acute lymphoblastic leukemia are characterized by a 9;22 chronosome translocation in which 5' sequences of the bcr gene become fused to the c-abl proto-oncogene. The resulting chimeric genes encode bcr/abl fusion proteins which have deregulated tyrosine kinase activity and appear to play an important role in induction of these leukemias. A series of bcr/abl genes were constructed in which nested deletions of the bcr gene were fused to the c-abl gene. The fusion proteins encoded by these genes were assayed for autophosphorylation in vivo and for differences in subcellular localization. Our results demonstrate that bcr sequences activate two functions of c-abl; the tyrosine kinase activity and a previously undescribed microfilament-binding function. Two regions of bcr which activate these functions to different degrees have been mapped: amino acids 1 to 63 were strongly activating and amino acids 64 to 509 were weakly activating. The tyrosine kinase and microfilament-binding functions were not interdependent, as a kinase defective bcr/abl mutant still associated with actin filaments and a bcr/abl mutant lacking actin association still had deregulated kinase activity. Modification of actin filament functions by the bcr/abl tyrosine kinase may be an important event in leukemogenesis.
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PMID:Activation of tyrosinase kinase and microfilament-binding functions of c-abl by bcr sequences in bcr/abl fusion proteins. 170 8

A monoclonal antibody (17F11) was raised by immunization of a Balb/c mouse with leukemic blasts from a patient with acute non-lymphocytic leukemia (ANLL). This antibody recognizes most leukemic blasts of myeloid but not of lymphoid lineage and no peripheral blood cells. By screening NIH-3T3 fibroblasts transfected with the human proto-oncogene c-kit (NIH-3T3/hckit) it could be shown that 17F11 specifically recognizes the gene product P145c-kit. Immunofluorescence analysis on normal hemopoietic cells revealed that 17F11 weakly stains 1-3% of bone marrow mononuclear cells (BMMNC). By FACS sorting and colony assays it could be shown that granulocyte--macrophage progenitor cells could be enriched 10-20-fold, granulocyte progenitors 50-80-fold, and erythroid and multipotential progenitor cells 15-20-fold, in the 17F11 positive fraction. Double fluorescence analysis revealed that P145c-kit is co-expressed on 40-60% of the CD34 positive BMMNC. Finally, these data show that P145c-kit is expressed on blast cells from most patients with ANLL (26/30) and chronic myeloid leukemia in blast crisis (7/9), but is absent on blasts from patients with acute lymphoblastic leukemia expressing the T-, B-lineage, or common ALL phenotypes.
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PMID:The product of the proto-oncogene c-kit (P145c-kit) is a human bone marrow surface antigen of hemopoietic precursor cells which is expressed on a subset of acute non-lymphoblastic leukemic cells. 172 Apr 90

By using antisense oligomers the functional role of the c-abl proto-oncogene in the in vitro growth of bone marrow hematopoietic progenitors from normal subjects and patients with chronic myelogenous leukemia (CML) has been evaluated. Light density bone marrow cells (LDBMs) were depleted of adherent cells, pre-incubated for 15 h with the appropriate oligomer at a concentration of 14 microns, and then plated in methylcellulose for the evaluation of colony formation. Both anti-exon Ia and anti-exon Ib antisense oligomers produced a significant inhibition of normal day 14 CFU-GM growth in vitro (n = 5, 41 +/- 11%, and 36 +/- 7%, respectively; p less than 0.01). In contrast, normal BFU-E growth was not significantly influenced by antisense oligomers (n = 5, 14 +/- 21% and 7 +/- 19%, respectively; p less than 0.05). These findings were confirmed by plating CD34 positive progenitors. When interleukin 3 (IL-3) (100 ng/ml) was added to the culture medium during the preincubation of LDBMCs, the inhibitory effects of antisense oligomers on normal CFU-GM growth were abolished. Seven patients with CML were also studied, all of whom had cytogenetic evidence of 100% clonal hematopoiesis. In five patients in the chronic phase, antisense oligomers were inhibitory on in vitro growth of both day 14 CFU-GM (37 +/- 20% and 37 +/- 15%, p less than 0.05) and BFU-E (45 +/- 15% and 41 +/- 11%, p less than 0.05), and this inhibition was not removed by pre-incubation with IL-3. No significant effect was observed on cluster or colony formation in two patients with CML in accelerated or blastic phase, and on in vitro growth of clonogenic cells from the Ph1-positive K-562 cell line. These findings (i) confirm previous observations showing a lineage specific requirement of c-abl function in normal hematopoiesis, and (ii) suggest that the residual c-abl expression has a role in chronic phase CML hematopoiesis, as its inhibition impairs both myeloid and erythroid colony formation in vitro.
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PMID:c-abl function in normal and chronic myelogenous leukemia hematopoiesis: in vitro studies with antisense oligomers. 173 9

Cancer is caused by specific DNA damage. Several common mechanisms that cause DNA damage result in specific malignant disorders: First, proto-oncogenes can be activated by translocations. For example, translocation of the c-myc proto-oncogene from chromosome 8 to one of the immunoglobulin loci on chromosomes 2, 14, or 22 results in Burkitt's lymphomas. Translocation of the c-abl proto-oncogene from chromosome 9 to the BCR gene located on chromosome 22 produces a hybrid BCR/ABL protein resulting in chronic myelogenous leukemia. Second, proto-oncogenes can be activated by point mutations. For example, point mutations of genes coding for guanosine triphosphate-binding proteins, such as H-, K-, or N-ras or G proteins, can be oncogenic as noted in a large variety of malignant neoplasms. Proteins from these mutated genes are constitutively active rather than being faithful second messengers of periodic extracellular signals. Third, mutations that inactivate a gene can result in tumors if the product of the gene normally constrains cellular proliferation. Functional loss of these "tumor suppressor genes" is found in many tumors such as colon and lung cancers. The diagnosis, classification, and treatment of cancers will be greatly enhanced by understanding their abnormalities at the molecular level.
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PMID:Molecular mechanisms of cancer. 181 12

The Bcl-2 proto-oncogene was discovered at the t(14;18) breakpoint found in most follicular B-cell lymphomas and some diffuse large-cell lymphomas. Bcl-2 is unique among proto-oncogenes, being localized to mitochondria and extending cell survival by blocking programmed cell death. We examined Bcl-2 protein expression in 82 hematologic malignancies and reactive lymphoid processes. All lymphomas with Bcl-2 rearrangement demonstrated high levels of Bcl-2 protein. However, most follicular and diffuse lymphomas without Bcl-2 rearrangement also displayed intense Bcl-2 staining. In these cases, mechanisms other than classic translocation may be deregulation Bcl-2. The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis. Small lymphocytic malignancies, including small lymphocytic lymphoma, mantle zone lymphoma, and chronic lymphocytic leukemia, expressed intermediate levels of Bcl-2. Bcl-2 protein varied in plasma cell dyscrasias. Bcl-2 protein levels in T-cell lymphomas reflected their corresponding stage of development. No substantial Bcl-2 was present in the Reed-Sternberg cells of nodular sclerosing Hodgkin's disease. Chronic myelogenous leukemia was strongly positive for Bcl-2, consistent with the presence of Bcl-2 in normal myeloid progenitors. Immunohistochemistry identified an expanded spectrum of hematopoietic neoplasms in which Bcl-2 may provide a cell survival advantage.
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PMID:Immunolocalization of the Bcl-2 protein within hematopoietic neoplasms. 186 40

Chronic myelogenous leukemia (CML) is the best understood human cancer. The molecular basis of CML involves activation of a cellular proto-oncogene--ABL. The consequence is to increase tyrosine kinase activity. This results in a marked clonal increase in the myeloid mass. Later on, cellular maturation is blocked and the decrease eventuates in acute leukemia. Abnormalities of other proto-oncogenes or antioncogenes, like P53, may be involved in leukemia progression. Treatment of CML involves chemotherapy and, more recently, interferon. Whether this treatment prolongs survival or increases the likelihood of cure is unknown but either result seems unlikely. Bone marrow transplants which cure about 50% of persons with CML are most effective when performed in chronic phase.
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PMID:Chronic myelogenous leukemia: molecule to man. 189 3


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