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 majority of patients with chronic myelogenous leukemia (CML) have a characteristic reciprocal translocation between chromosome 9 and 22, resulting in the Philadelphia (Ph1) chromosome. During this translocation, the c-abl oncogene on chromosome 9 is transferred to the Ph1 chromosome and linked to a breakpoint cluster region (bcr), which is part of a large bcr gene. This phenomenon results in the formation of a bcr-c-abl fusion gene, which is transcribed into an 8.5 kb chimeric mRNA encoding a 210 kd bcr-c-abl fusion protein. The fusion protein has tyrosine kinase activity implicated in the pathogenesis of CML. The breakpoint near the c-abl locus on chromosome 9 can occur within a large area. In contrast, the breakpoints on chromosome 22 cluster within the bcr region of 5.8 kb. A chronic phase lasts for an average of 2 to 3 years; and, subsequently, most patients enter blast crisis. In the present study, we examined 15 Ph1-positive CML patients (eight in chronic phase, one in accelerated phase, and six in blast crises) as to whether the identifiable difference in the locations of the bcr breakpoints exist between CML patients in chronic phase and those in blast crisis. In seven of eight CML patients in chronic phase, in one in accelerated phase, and in four out of six CML patients in blast crisis, the bcr breakpoints clustered in the 3' portion of the bcr. Thus, we could not find out the correlation between the locations of the bcr breakpoints and the clinical stage of the CML patients. This might imply that blastic transformation in Ph1-positive CML was caused by other mechanisms than the transition of the bcr breakpoints.
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PMID:No correlation between locations of bcr breakpoints and clinical states in Ph1-positive CML patients. 273 54

The Philadelphia chromosome (t9:22;q34:q11) is found in more than 90% of patients with chronic myelogenous leukemia, in 10 to 20% of patients with acute lymphocytic leukemia, and in 1 to 2% of patients with acute myelogenous leukemia. Alternative chimeric oncogenes are formed by splicing different sets of BCR gene exons on chromosome 22 across the translocation breakpoint to a common set of ABL oncogene sequences on chromosome 9. This results in an 8.7-kilobase mRNA that encodes the P210 BCR-ABL gene product commonly found in patients with chronic myelogenous leukemia or a 7.0-kilobase mRNA that produces the P185 BCR-ABL gene product found in most Philadelphia chromosome-positive patients with acute lymphocytic leukemia. To compare the efficiency of growth stimulation by these two proteins, we derived cDNA clones for each with identical 5' and 3' untranslated regions and expressed them from retrovirus vectors. Matched stocks were compared for potency to transform immature B-lymphoid lineage precursors. The growth-stimulating effects of P185 for this cell type were found to be significantly greater than those of P210. Structural changes in BCR may regulate the effectiveness of the ABL tyrosine kinase function, as monitored by lymphocyte growth response. Changes in mitogenic potency may help to explain the more acute leukemic presentation usually associated with expression of the P185 BCR-ABL oncogene.
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PMID:Alternative forms of the BCR-ABL oncogene have quantitatively different potencies for stimulation of immature lymphoid cells. 274 38

Herbimycin A, a benzoquinonoid ansamycin antibiotic, is found to reduce intracellular phosphorylation by tyrosine protein kinase. The human chronic myelogenous leukemia cell line K562 expresses a structurally altered c-abl protein with tyrosine kinase activity. When K562 cells are induced to undergo erythroid differentiation by hemin, reduction in the intracellular level of tyrosine phosphorylation occurs. In order to understand the relationship between induction of differentiation and reduction of tyrosine phosphorylation by the c-abl gene product, the effect that herbimycin A, a selective inhibitor of intracellular tyrosine kinase activity, exerts on the differentiation of K562 cells was examined. Reduction of tyrosine phosphorylation in K562 cells by herbimycin A was observed within 1 h. Noncytotoxic concentrations of herbimycin A induced erythroid differentiation of K562 cells but not of murine erythroleukemia 745A cells. The other human myeloid leukemia cell lines (HL-60, THP-1, and U937) tested were not induced to undergo cell differentiation by this antibiotic. Herbimycin A and the other well-known inducers such as hemin, butyric acid, Adriamycin, and 1-beta-D-arabinofuranosylcytosine had additive or more than additive effects on induction of erythroid differentiation of K562 cells. With respect to inhibition of cell growth, the sensitivity of K562 cells to herbimycin A was highest in the human leukemia cell lines we tested. Noncytotoxic concentrations of herbimycin enhanced the antiproliferative effect of Adriamycin or 1-beta-D-arabinofuranosylcytosine on K562 cells. Combination therapy with herbimycin A and its derivatives may be considered for use in the treatment of some types of leukemia where tyrosine kinase activities are implicated as determinants of the oncogenic state.
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PMID:Induction of erythroid differentiation of K562 human leukemic cells by herbimycin A, an inhibitor of tyrosine kinase activity. 291 Apr 52

The Philadelphia chromosome (Ph) is an abbreviated chromosome number 22 resulting, in the majority of cases, from a balanced translocation between the 9 and 22 long arms. It is considered a marker of chronic myeloid leukemia and its diagnostic and prognostic value in this disease has been demonstrated. It is also present in a number of patients with acute leukemias of poor prognosis. The Ph arises in a bone marrow progenitor cell and seems to allow the clonal expansion of the malignant cells. The typical 9;22 translocation results in the transposition of the cellular oncogene Abelson in close proximity of chromosome 22 linked critical sequences. This structural change leads to the transcription of an hybrid mRNA coding for an abnormal protein with a tyrosine kinase activity which could play a major role in the leukemogenesis process.
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PMID:[The Philadelphia chromosome: clinical and biological significance]. 294 11

The consistent cytogenetic translocation of chronic myelogenous leukemia (the Philadelphia chromosome, Ph1) has been observed in cells of multiple hematopoietic lineages. This translocation creates a chimeric gene composed of breakpoint-cluster-region (bcr) sequences from chromosome 22 fused to a portion of the abl oncogene on chromosome 9. The resulting gene product (P210c-abl) resembles the transforming protein of the Abelson murine leukemia virus in its structure and tyrosine kinase activity. P210c-abl is expressed in Ph1-positive cell lines of myeloid lineage and in clinical specimens with myeloid predominance. We show here that Epstein-Barr virus-transformed B-lymphocyte lines that retain Ph1 can express P210c-abl. The level of expression in these B-cell lines is generally lower and more variable than that observed for myeloid lines. Protein expression is not related to amplification of the abl gene but to variation in the level of bcr-abl mRNA produced from a single Ph1 template.
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PMID:Variable expression of the translocated c-abl oncogene in Philadelphia-chromosome-positive B-lymphoid cell lines from chronic myelogenous leukemia patients. 301 46

Activation of the oncogenic potential of c-abl proto-oncogene has been correlated with the activation of its tyrosine kinase activity. The oncogenes derived from c-abl, e.g., gag/v-abl in Abelson murine leukemia virus or bcr/abl in chronic myelogenous leukemia, lack N-terminal coding sequences of the normal c-abl gene. In mouse and human cells, two sets of N-terminal amino acids encoded by 5'-variable exons are found in c-abl proteins. To assess the importance of N-terminal deletion in the activation of c-abl tyrosine kinase, a full length or an N-terminal deleted c-abl protein was expressed in bacteria and in monkey COS cells. Measurements of the autokinase activity of these two c-abl proteins showed that deletion of the N-terminal amino acids led to a three to five fold increase of the c-abl tyrosine kinase activity. Thus, the N-terminal deletion is important in the activation of c-abl proto-oncogene.
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PMID:Negative regulation of c-abl tyrosine kinase by its variable N-terminal amino acids. 314 98

The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.
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PMID:Rearrangement of the breakpoint cluster region and expression of P210 BCR-ABL in a "masked" Philadelphia chromosome-positive acute myeloid leukemia. 317 49

We report a case of acute leukemia in which studies at presentation showed both myeloid and lymphoid cell surface markers. At relapse membrane markers studies were consistent with a leukemia of B-lymphoid lineage. However, immunoglobulin (Ig) and T cell receptor (TCR) beta chain genes were both found in a rearranged configuration. The majority of metaphases from the leukemic cells at presentation showed the Philadelphia chromosome, t(9;22)(q34;q11), whereas a minority were normal. At relapse both Ph-positive and -negative metaphases were still present in the bone marrow but some of the Ph-negative metaphases had acquired an additional chromosome #19 [47,XY, + 19]. Southern analysis of DNA from leukemic bone marrow cells at diagnosis showed no rearrangement of breakpoint cluster region (bcr). There was no bcr-abl chimeric mRNA typical of Ph-positive chronic myeloid leukemia (CML). However, the cells expressed an abl-related protein of Mr 190 kd with enhanced tyrosine kinase activity. Leukemic cell metaphases were studied by the technique of in situ hybridization with probes for C-lambda, sis, abl, and 5' bcr. The c-abl probe mapped to chromosome 22q11 in Ph-positive metaphases. The 5' bcr probe mapped to 9q+ in the Ph-positive metaphases and the C-lambda gene mapped to the Ph chromosome. Thus, the genomic breakpoint in this patient must lie upstream of the BCR defined by study of Ph-positive CML and downstream of the C-lambda gene locus. We speculate that the Ph-negative cells in this patient may represent a leukemic proliferation susceptible to acquisition of specific chromosomal changes.
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PMID:The genomic breakpoint in a patient with Philadelphia-positive acute leukemia is 5' of the breakpoint cluster region. 325 55

In this review we have described molecular consequences of the t(9;22) translocation typical of CML and some cases of ALL. This data indicates an important role for abl and bcr and suggest some common mechanisms of activation of c-abl related tyrosine kinase activity. This data also provides insight into the relationship between Ph1 positive, Ph1 negative CML and Ph1 positive ALL. Although this data answers some questions, they raise others; eg, what is the molecular basis of the t(9;22) translocation? How does increased abl related kinase activity eventuate in CML? Finally, this data reviewed suggests that factors other than abl and bcr must play a role in CML. Definition of these factors will be important in the future.
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PMID:Molecular biology of chronic myelogenous leukemia. 327 14

The ABL proto-oncogene on the Philadelphia chromosome is 'activated' by its translocation in a manner similar to its activation by the murine Abelson leukemia virus--with the formation of a fusion protein with a new N-terminus and enhanced tyrosine kinase activity. Study of this BCR-ABL fusion gene has led to the development of molecular probes which are beginning to play an important role in the diagnosis and clinical management of chronic myelogenous leukemia, and may ultimately lead to better understanding of the biology of the disease. The role of ABL on the Philadelphia chromosome in acute lymphoblastic leukemia is only now beginning to be understood, but is likely to be similar, and a new ABL species has already been identified by several groups. It is likely that this protein is the product of a fusion gene, as it is in chronic myelogenous leukemia, but definitive proof awaits molecular cloning of the translocation breakpoint. Aside from its activation by the Ph1 chromosome, ABL has not been found to have a role in any other human cancer.
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PMID:The ABL oncogene in human leukemias. 328 49


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