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)

An altered c-abl gene product (P210bcr-abl) possessing associated tyrosine protein kinase activity was recently been reported in several blast chronic myelogenous leukemia (CML) cell lines. We have examined different morphological types of leukocytes directly obtained from patients at the blast crisis stage of CML for expression of P210bcr-abl tyrosine protein kinase activity. Phosphorylation of P210bcr-abl in an immune complex kinase assay using an anti-v-abl peptide serum was observed in blast cells from four Philadelphia chromosome (Ph1)-positive CML patients in blast crisis. P210bcr-abl protein kinase activity was detected regardless of whether the blast cells were of myeloid, lymphoid, or undifferentiated morphology. P210bcr-abl protein kinase activity was not detected in immune complexes either from leukocytes of four Ph1-negative CML patients in blast crisis, of five acute myelogenous leukemia patients, or in the promyelocytic cell line HL-60. Mature myeloid cells are associated with an inhibitory factor for not only P210bcr-abl protein kinase activity, but also protein kinases in general. Therefore, analyses of Ph1-positive benign phase CML myeloid cells, the majority of which are well differentiated, could not be successfully performed. The inhibition of P210bcr-abl protein kinase activity is not a specific property of mature cells from CML patients since granulocytes from a normal volunteer also demonstrated a similar effect. However, extracts of Ph1-positive cultured B-lymphocytes from a patient in benign phase demonstrated active P210bcr-abl protein indicating that the P210bcr-abl protein is expressed in an enzymatically active form in the earlier phases of CML. In addition to the previously reported P210 and P190 abl-related proteins, a novel Mr 53,000 protein was found to undergo phosphorylation at serine and tyrosine in immune complex kinase assays of two blast crisis CML cell lines (K562 and EM2) and in samples from blast crisis patients in which P210bcr-abl was detected. Peptide mapping by the Cleveland technique suggested that Mr 53,000 protein is unrelated to P210bcr-abl. Immune complex kinase assays of K562 cells with an anti-src serum (GD-11) yielded active c-src kinase and a Mr 50,000 phosphorylated protein, both of which were resistant to alkaline hydrolysis. Peptide mapping suggested that Mr 53,000 protein is related to Mr 50,000 protein which is precipitated with P210bcr-abl as an Mr 300,000 protein complex.
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PMID:Analysis of P210bcr-abl tyrosine protein kinase activity in various subtypes of Philadelphia chromosome-positive cells from chronic myelogenous leukemia patients. 243 23

The great majority of patients with chronic myeloid leukaemia (CML) have a Philadelphia (Ph) chromosome which has proved at molecular level to be associated with the production of chimeric BCR-ABL gene which in turn is expressed as a fusion protein (P210) with tyrosine kinase activity. An equivalent but somewhat smaller chimeric gene and fusion protein (P190) is found in some cases of Ph-positive acute leukaemia. Though the consistency of these abnormal findings in patients with Ph-positive leukaemia is strong evidence for their pathogenetic role, there are still many unanswered questions.
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PMID:Recent advances in molecular biology of chronic myeloid leukaemia: is the pathogenetic puzzle approaching solution? 249 82

Philadelphia chromosome positive acute lymphocytic leukemia and chronic myelogenous leukemia are strongly associated with two distinct forms of bcr-abl chimeric protein, known as P190 and P210, respectively. By studying cDNA clones obtained from the cell line KBM-5, we identified two new bcr-abl transcripts. These are formed by alternative splicing of at least two exons to the known bcr exon 2. One novel transcript can encode a protein kinase of approximately 190 kd, while the other can direct the synthesis of a larger protein whose amino terminus remains to be defined. The alternative exons can be spliced also to the two normal bcr transcripts, reflecting the activation of a cryptic promoter. These messages were present at low abundance in two cases of blastic crisis but were not detected in the chronic phase. It is conceivable that the proteins encoded by the new bcr-abl mRNAs are involved in the transformation to the acute phase in some cases of chronic myelogenous leukemia.
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PMID:Alternative 5' end of the bcr-abl transcript in chronic myelogenous leukemia. 291 4

Three antisera against the mouse v-abl gene product were used to identify two potential human c-abl gene products in the chronic myelogenous leukemia cell line K562. Two antipeptide sera were generated in rabbits using the predicted amino acid sequence of the mouse v-abl gene product. One antiserum was made against a polypeptide overlapping the in vivo tyrosine phosphorylation site of murine P120gag-abl and what is believed to be a homologous tyrosine phosphorylation site of the predicted normal human c-abl gene product (v-abl 263-280). The second antipeptide serum, abl 389-403, was generated against a predicted hydrophilic peptide of the v-abl gene product. Immunoprecipitation from K562 cells metabolically labeled with [32P]orthophosphate by a mouse tumor regressor and abl 389-403 antipeptide sera detected two proteins of 190,000 and 240,000 Da. Both proteins were labeled primarily at serine and, to a much lesser extent, at tyrosine residues. Immune complex kinase assays using conditions that allow the tyrosine phosphorylation of P120gag-abl showed that in vitro phosphorylation of P190 and P240 occurs primarily at tyrosine residues. The detection of these enzymatically active human c-abl gene products is a rare observation which may be in part attributed to the c-abl gene translocation from chromosomes 9 to 22 occurring in the vast majority of chronic myelogenous leukemia patients.
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PMID:The human cellular abl gene product in the chronic myelogenous leukemia cell line K562 has an associated tyrosine protein kinase activity. 298 32

Philadelphia (Ph1) chromosome breakpoints in acute lymphoblastic leukemia (ALL) are of two kinds: those within the breakpoint cluster region (bcr+), as in chronic myeloid leukemia (CML), and those outside it (bcr-). These encode different c-abl messenger RNAs (mRNAs), p210 and p190, respectively. It has been suggested that one class of Ph+ ALL (bcr+) may be a variant of CML arising in a multipotent stem cell, the other (bcr-) de novo ALL initiated in a lymphoid-committed progenitor. Thirty-two cases of ALL (12 Ph1+, ten chromosomally normal, and ten non-mitotic cases) were investigated for bcr involvement. Breakpoints were found within five Ph1+ and in one normal case. There was no difference in clinical features, common ALL antigen (CALLA) positivity, cytogenetics, or response to treatment between the 6 bcr+ and 7 Ph1+ bcr- patients. Myeloid antigen expression was found in 2 bcr+ cases. Bcr rearrangement appeared to be restricted to the lymphoblastic component of marrow or blood in at least four bcr+ cases. In one case, separated myeloid and lymphoid cell fractions were both bcr+. Potential heterogeneity of the Ph1+ target cell, as seen in this study, may be more important in determining disease outcome than the precise location of the Ph breakpoint.
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PMID:Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. 316 1

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

The mAb A6 was produced by immunization of mice with human PHA-stimulated PBMC. Immunoprecipitation studies and staining of cell lines transfected with individual leukocyte common antigen (LCA) isoforms showed that A6 recognizes a unique epitope strongly expressed on the lower MW isoform (p180) of LCA, but also weakly expressed on the p190 isoform coded by exon B and the p205 coded by exons A and B. The epitope recognized by A6 was carbohydrate-dependent in that it was neuraminidase-sensitive, but trypsin-resistant. A6 strained most TCR-alpha beta+ cells with differential intensities, subdividing them into a bright and dim population, and strongly stained all TCR-gamma delta+ cells. A6 did not stain CD19+ B cells nor CD56+ NK cells. Anti-CD45 mAb such as UCHL1 recognizing CD45RO have been used to define memory T cells. Depletion of PBMC subsets with A6 or UCHL1 mAb dramatically decreased proliferative responses to the recall antigens anti-CD3 mAb and alloantigen and enhanced their responses to PHA. A6, unlike UCHL1, also depleted alloreactive T cells that affect primary and secondary MLC and CML. Thus, A6 was shown to recognize the lower MW isoforms of LCA which are expressed on functional T cell subsets including memory, activated, and alloreactive T cells.
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PMID:A monoclonal antibody (A6) recognizing a unique epitope restricted to CD45RO and RB isoforms of the leukocyte common antigen family identifies functional T cell subsets. 752 74

We investigated the breakpoints of the bcr gene in 46 Ph1-positive CML cases by Southern blot analysis of bcr rearrangement, and in 17 CML cases by a combination of Southern blot analysis and RT-PCR. By Southern blot, the breakpoint was not identified on M-bcr in three CML cases, of which one case showed the P210-type bcr/abl transcript and two cases showed the ALL-type (P190-type) bcr/abl transcript with or without P210 transcript. Later two cases showed unique hematological profiles such as thrombocytosis, mild myelofibrosis, and relative resistance to alkylating agents. Therefore, the present study suggests that expression of the P190-type transcript may affect clinical and hematological findings in CML.
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PMID:Chronic myeloid leukemia presenting ALL-type BCR/ABL transcript. 794 5

The p210bcr/abl tyrosine kinase appears to be responsible for initiating and maintaining the leukemic phenotype in chronic myelogenous leukemia (CML) patients. p21ras-p120GAP interactions play a central role in transducing mitogenic signals. Therefore, we investigated whether p21ras and p120GAP are regulated by p210bcr/abl, and whether this activation is functionally significant for CML cell proliferation. We report that transient expression of p210bcr/abl in fibroblast-like cells induces simultaneous activation of p21ras and inhibition of GTPase-promoting activity of p120GAP, and confirm these data showing that downregulation of p210bcr/abl expression in CML cells with bcr/abl antisense oligodeoxynucleotides induces both inhibition of p21ras activation and stimulation of GTPase-promoting activity of p120GAP. Tyrosine phosphorylation of two p120GAP-associated proteins, p190 and p62, which may affect p120GAP activity, also depends on p210bcr/abl tyrosine kinase expression. Direct dependence of these effects on the kinase activity is proven in experiments in which expression of c-MYB protein in fibroblast-like cells or downregulation of c-MYB expression resulting in analogous inhibition of CML cell proliferation does not result in the same changes. Use of specific antisense oligodeoxynucleotides to downregulate p21ras expression revealed a requirement for functional p21ras in the proliferation of Philadelphia chromosome-positive CML primary cells. Thus, the p210bcr/abl-dependent regulation of p120GAP activity is responsible, in part, for the maintenance of p21ras in the active GTP-bound form, a crucial requirement for CML cell proliferation.
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PMID:Negative regulation of p120GAP GTPase promoting activity by p210bcr/abl: implication for RAS-dependent Philadelphia chromosome positive cell growth. 819 13

We have developed a system for expressing bcr/abl genes in the mouse hematopoietic system utilizing retroviral gene transfer and bone marrow transplantation. Expression of the P210bcr/abl gene in mice gives rise to a spectrum of hematological malignancies, most prominently a myeloproliferative syndrome which closely resembles human chronic myelogenous leukemia (CML). Studies of this system and related systems in other laboratories have begun to yield insights into the pathophysiology of the human bcr/abl leukemias. The CML-like syndrome appears to be a consequence of infection of a multipotential hematopoietic progenitor target cell. The leukemic clone is difficult to transplant to secondary recipients, but undergoes evolution to acute leukemia. The P190 form of bcr/abl appears to be more potent in leukemogenesis than P210, but may also be associated with a CML-like picture upon infection of a multipotential target cell. There may be a spectrum of different chronic phase duration associated with different Bcr/Abl proteins, with bcr sequences influencing the rate of disease progression. In mice, duplication or alterations of the bcr/abl gene itself may constitute a major mechanism of disease progression.
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PMID:Disease progression in a murine model of bcr/abl leukemogenesis. 825 3


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