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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 myelogenous leukaemia is a clonal neoplasm of the pluripotent haematopoietic stem cell which is characterized in most patients by a consistent cytogenetic abnormality known as the Philadelphia chromosome. This chromosome occurs as a consequence of a reciprocal translocation between the long arms of chromosomes 9 and 22 which results in the creation of a new gene comprising sequences from the c-abl gene on chromosome 9 and the bcr gene on chromosome 22. The protein encoded by this structurally altered hybrid gene differs from the normal c-abl gene product in both molecular weight and in tyrosine kinase activity. It is likely that these alterations in the c-abl gene product play a central role in the pathogenesis of this leukaemia.
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PMID:Molecular pathogenesis of chronic myelogenous leukaemia. 130 82

The hallmark of chronic myelogenous leukemia is the translocation of the human c-abl protooncogene (ABL) from chromosome 9 to the specific breakpoint cluster region (bcr) of the BCR gene on chromosome 22. The t(9;22)(q34;q11) translocation results in the formation of a BCR-ABL fusion gene that encodes a 210-kDa chimeric protein with abnormal tyrosine kinase activity. The ABL and BCR genes are expressed by normal cells and thus the encoded proteins are presumably nonimmunogenic. However, the joining-region segment of the p210BCR-ABL chimeric protein is composed of unique sequences of ABL amino acids joined to BCR amino acids that are expressed only by malignant cells. The current study demonstrates that the joining region of BCR-ABL protein is immunogenic to murine T cells. Immunization of mice with synthetic peptides corresponding to the joining region elicited peptide-specific, CD4+, class II major histocompatibility complex-restricted T cells. The BCR-ABL peptide-specific T cells recognized only the combined sequence of BCR-ABL amino acids and not BCR or ABL amino acid sequences alone. Importantly, the BCR-ABL peptide-specific T cells could recognize and proliferate in response to p210BCR-ABL protein. The response of peptide-specific T cells to protein demonstrated that p210BCR-ABL can be processed by antigen-presenting cells so that the joining segment is bound to class II major histocompatibility complex molecules in a configuration similar to that of the immunizing peptide and in a concentration high enough to stimulate the antigen-specific T-cell receptor. Thus, BCR-ABL protein represents a potential tumor-specific antigen related to the transforming event and shared by many individuals with chronic myelogenous leukemia.
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PMID:T-cell immunity to the joining region of p210BCR-ABL protein. 134 32

The hallmark of chronic myelogenous leukemia (CML) is the Philadelphia chromosome (Ph1) which is caused by a translocation of the c-abl gene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22. Polymerase chain reaction (PCR) can be used to detect the chimeric bcr/c-abl mRNA as evidence of the translocation. We applied a very simple and quick method of isolating cytoplasmic RNA, as well as reverse transcription and PCR in detecting bcr/c-abl mRNA of seven CML patients in various stages. Our results showed that only a small amount of either peripheral blood or bone marrow material was required for the expression of the bcr/c-abl mRNA. This is a very fast and time-saving method since a one-step method of cytoplasmic RNA isolation is used instead of the several steps in total RNA isolation as published in other literature.
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PMID:Detection of bcr/c-abl mRNA in chronic myelogenous leukemia by polymerase chain reaction to identify chromosome translocation. 135 83

The observation made over 30 years ago that the Philadelphia chromosome is present in nearly all patients with CML led to the identification of a novel fusion gene bcr-abl. In the past few years, the biochemical and biological properties of bcr-abl have been extensively explored. Bcr sequences appear to activate c-abl for transformation by binding to the SH2 domain of c-abl in an intramolecular interaction, presumably interfering with the adjacent SH3 regulatory domain. Upon introduction into bone marrow cells, bcr-abl can cause acute or chronic leukaemias in mice and can stimulate the growth of many cell types, including multipotent stem cells, in vitro. Although their growth is stimulated, these cells are not fully malignant blastic leukaemias. The molecular events that occur during the progression to blast crisis of CML remain largely undefined, but existing animal models and in vitro culture systems will be useful for identifying or testing candidate genes. The study of tyrosine kinase oncogenes in general will probably lead to the identification of relevant bcr-abl substrates. The elucidation of these molecules as well as more downstream events in the bcr-abl signalling pathway offers the hope for novel therapeutic interventions to control Philadelphia chromosome leukaemias.
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PMID:The bcr-abl gene in chronic myelogenous leukaemia. 145 Nov 13

Chronic myelogenous leukemia (CML) is characterized by a translocation involving the c-abl protein-tyrosine kinase gene. A chimeric mRNA is formed containing sequences from a chromosome 22 gene (bcr) at its 5' end and all but the variable exon 1 of c-abl sequence. The product of this mRNA, p210bcr-abl, has constitutively high protein-tyrosine kinase activity. We examined K562 cells and other lines established from CML patients for the presence of phosphotyrosine (P-Tyr)-containing proteins which might be p210bcr-abl substrates. Two-dimensional gel separation of 32P-labeled proteins followed by phosphoamino acid analysis of 25 phosphoproteins, which comprised the major alkali-stable phosphoproteins, indicated that three related proteins of 41 kDa are the most prominent P-Tyr-containing proteins detected by this method. The 41-kDa phosphoproteins are found in two other CML lines that we examined but not in lines of similar lineage isolated from patients with distinct leukemic disease. A protein that comigrates with the major form of pp41 (pp41A) and contains P-Tyr is also found in murine fibroblasts and B-lymphoid cells transformed by Abelson murine leukemia virus, which encodes the v-abl protein, and in platelet-derived growth factor-treated fibroblasts, in which it has been described previously. We analyzed three pairs of Epstein-Barr virus-immortalized B-cell lines from individual CML patients and found that only the lines in which active p210bcr-abl was present contained detectable pp41. We also performed immunoblotting with anti-P-Tyr antibodies on the same CML cell lines and detected at least four other putative substrates of p210bcr-abl, which were undetected with use of the two-dimensional gel technique.
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PMID:A 41-kilodalton protein is a potential substrate for the p210bcr-abl protein-tyrosine kinase in chronic myelogenous leukemia cells. 154 12

The enhancers of several distinct viruses contain a common functional element, termed EP. This element binds ubiquitous cellular proteins and generates specific complexes in gel retardation analysis. Ultraviolet cross-linking and Southwestern analysis showed that a 140 kd polypeptide is the major EP DNA-binding protein. Using a combination of DNA binding and immunological techniques, we have identified the c-abl protein in a nuclear complex that binds to the EP element. abl was found to have both a specific and high affinity DNA binding activity. The ability to bind DNA is abolished in the mutant abl protein, p210bcr-abl, consistent with its cytoplasmic localization in chronic myelogenous leukemia.
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PMID:c-abl has a sequence-specific enhancer binding activity. 159 75

The Philadelphia chromosome, originally thought to be associated solely with chronic myelogenous leukemia (CML), has since been identified in acute leukemias and in some cases of lymphoma. The Philadelphia chromosome results from reciprocal translocation of genetic material between chromosome 9 and 22 involving the c-abl and BCR genes respectively. Southern blot analysis of the BCR genes was carried out on biopsy specimens from 49 patients presenting with malignant lymphoma without a previously documented CML phase. In two patients, BCR gene rearrangements were detected in the malignant lymph nodes but not in the bone marrow samples. A third patient showed BCR gene rearrangements in the bone marrow but not in the lymph node. From this limited study, it seems that the overall incidence of BCR gene rearrangement in malignant lymphoma is similar to that observed in adult AML.
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PMID:Rearrangement of BCR genes in malignant lymphoma. 160 94

The first clear cut association of an oncogene with a specific cancer is the c-abl translocation in chronic myelogenous leukemia and acute lymphocytic leukemia; it has been observed in 90% of CML cases examined. This is the major contributing factor to its being the target of the first oncogene-based FDA-approved diagnostic test. Although the role of the abl translocation in the tumorigenic process is not yet understood, it is clear that somehow it must be causally related to the disease, and thus is an ideal target for a diagnostic test. The association of this oncogene with a specific cancer is the model on which all others may be based in the future. Second generation tests could easily include PCR on mRNA, and/or in situ hybridization, both of which could be performed using blood samples. Both methods would provide a faster means of testing a large number of cells, however, the methodologies must be improved through automation and computer-aided image analysis, respectively, in order to become useful routine tests. Both neu and epidermal growth factor receptor (EGFR) appear to have a close correlation between overexpression of the gene product and outcome of disease in breast cancer; valuable information for prognosis of the disease. And again, although the actual mechanism of action of these molecules and how this relates to the tumorigenic process is not yet known, it is believed from the very nature of the molecules that they must in some way contribute to the progression of the disease. In both cases, the protein products are overexpressed in tissue, and in the case of Neu, it appears as through at least some of the patients have a Neu-related protein in their serum. These molecules present relatively easy targets for the development of diagnostic/prognostic assays, as antibodies are easily made and can be incorporated into a variety of assay formats. Current assays available, an ELISA for Neu and a radio-ligand binding assay for EGFR, are highly sensitive, reproducible and relatively easy to perform. Only the ELISA is commercially available, however, and hence allows for easy comparison between laboratories. An abvious step towards the routine measurement of EGFR then is the development of a comparable commercially available test. An improvement for both types of assay would be the incorporation of an internal control to gauge the cellular component of the tissue samples that are tested. The outcome of the applications of myc and ras to cancer diagnostics is not so easily predictable, with a couple of exceptions.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Diagnostic utility of oncogenes and their products in human cancer. 168 91

The usefulness of phosphotyrosine antibodies for the detection of physiologically regulated or deregulated tyrosine kinases is discussed in this report. This rather rare enzymatic activity is shared by receptors for some polypeptide growth factors and by the products of Class 1 oncogenes. The antibodies are able to detect proteins phosphorylated on tyrosine in fibroblasts stimulated with growth factors such as EGF and PDGF. The major phosphorylated protein species are the receptors themselves, which undergo phosphorylation only after the addition of the exogenous factor and only transiently. Phosphotyrosine antibodies were able to detect the products of the retroviral Class 1 oncogenes, which are endowed with deregulated tyrosine kinase activity. In fact, in these cases a constitutive phosphorylation of the relevant proteins was observed, which occurred continuously and independently of the presence or lack of exogenous ligands. A tyrosine kinase constitutively activated in human gastric carcinoma cells was detected by P-Tyr antibodies. This molecule has been characterized at the molecular level, and the mechanisms responsible for its enzymatic activation have been investigated. The question of whether the tyrosine kinase identified is responsible for the induction and the maintenance of the transformed phenotype in gastric carcinomas remains to be answered. It is reasonable to suggest that this might be the case by analogy with other situations such as Class 1 oncogenes activated by transduction by retroviruses, abnormal expression of EGF receptors, or deregulated activity of c-abl-encoded proteins in chronic myelogenous leukemia and acute lymphoblastic leukemia. Thus, the search for deregulated kinases by means of phosphotyrosine antibodies seems to be useful for identifying new activated oncogenes in clinical oncology.
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PMID:Tyrosine kinase and control of cell proliferation. 170 Dec 90

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


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