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 Philadelphia (Ph) translocation in CML is molecular-genetically characterized by a rearrangement of the c-abl oncogene with sequences of the bcr gene on the Ph chromosome. In leukemic cells this recombination results in the transcription of a 8.5 kb bcr/c-abl hybrid RNA which is translated into a p210 abl protein. The p210 abl protein contains, in contrast to its normal 145 abl counterpart, associated tyrosine kinase activity which is not physiologically controlled. Both genes do not participate in the acceleration of CML from chronic state into blast crisis. The majority of CML patients without cytogenetically detectable Ph chromosome also lack a bcr/abl rearrangement. However, some cases of Ph-negative CML could be reclassified into the group of Ph-positive CML by demonstration of a bcr gene rearrangement. One patient exhibited a bcr gene recombination without translocation of c-abl sequences. A similar heterogenous pattern is observed in Ph-positive acute leukemias. About 50% of cases are characterized by a bcr/abl rearrangement, as is likewise observed in Ph-positive CML. It is tempting to speculate that these patients represent Ph-positive CML cases that initially presented themselves for treatment with CML blast crisis. Particularly in pediatric Ph-positive ALL, the majority of cases show a c-abl oncogene translocation without bcr rearrangement. Precise molecular-genetic analyses of those cases are still pending. Molecular-genetic analyses have already been proven to be of clinical value 1) in the diagnosis of Ph-positive CML in the absence of cytogenetic methods, 2) in the subclassification of Ph-negative CML or Ph-positive acute leukemias.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Molecular genetics of the pathogenesis and classification of chronic myelocytic leukemia]. 330 31

Kinases which phosphorylate proteins on tyrosine residues are of importance in the control of both normal and malignant cell proliferation. The receptors for a number of growth factors have intracellular domains with tyrosine protein kinase activity and several viral oncogenes code for tyrosine protein kinases. An abnormal tyrosine protein kinase has been implicated in the pathogenesis of chronic granulocytic leukemia. Using an immunoblot method and an antiphosphotyrosine antibody, we have detected substrates of tyrosine protein kinases in fresh human leukemia cells and normal blood and bone marrow cells. These substrates were present in all types of cells examined. Cells from patients with acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia contain prominent phosphotyrosine-containing protein bands with molecular weights in excess of 95 kDa. By contrast, chronic granulocytic leukemia cells, as well as normal bone marrow cells, lymphocytes, and monocytes, contain predominantly low molecular weight (less than 95 kDa) tyrosine kinase substrates. When lymphocytes were stimulated to enter cell cycle, however, high molecular weight substrates of similar molecular weights to those detected in acute lymphoblastic leukemia, acute myeloid leukemia, and chronic lymphocytic leukemia became prominent. The implications of these findings in the control of normal and malignant cell proliferation and differentiation are discussed.
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PMID:Detection of tyrosine protein kinase substrates in fresh leukemia cells and normal blood cells using an immunoblotting technique. 331 58

A great deal of information has emerged over the past decade regarding the gene structures and corresponding protein products of the cellular and transformation-associated forms of the ABL tyrosine kinase family. Many reports have also detailed the biological effects of these proteins (particularly the viral ABL forms) on a broad range of cell types. However, in spite of all these research efforts, the precise role of the ABL gene in normal and neoplastic growth remains to be determined. To elucidate the mechanism of action of normal and altered ABL proteins, it is imperative to identify their relevant cellular substrates and establish the role of the ABL target proteins in transformation and normal cellular growth. The availability of temperature-sensitive ABL proteins, coupled with the use of sensitive anti-phosphotyrosine antibodies, should be useful in this respect. Purification of enzymatically active, intact forms of the ABL proteins produced in insect cells by employing baculovirus expression vectors should permit direct comparison of the biochemical properties and tertiary structures of the various members of the ABL protein kinase family. Such studies will aid in understanding the nature of the alteration of ABL which results in the activation of its transforming potential. Furthermore, the availability of purified ABL proteins should permit examination of interactions of ABL with other growth-regulatory proteins, such as growth factor receptors. It has been shown that transformation-associated ABL proteins interact with the IL-3, IL-2 and GM-CSF growth-factor pathways. These and other components of the cellular signalling pathways are potential ABL targets. The elucidation of ABL function by a variety of approaches such as those described above will ultimately aid in the development of far-reaching therapeutic treatments for at least two forms of human leukaemia: Ph positive CML and Ph positive ALL.
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PMID:Role of the ABL oncogene tyrosine kinase activity in human leukaemia. 333 51

The Ph chromosome is the hallmark of CML, where it is found in more than 90% of the cases. Cytogenetically, it usually results from a t(9;22)(q34;q11). The Ph arises in a stem cell and in chronic phase is found in all haematopoietic cell lineages, although it causes only increased granulopoiesis, and sometimes increased thrombopoiesis; furthermore blast crisis may occur in all differentiative patterns of the pluripotent stem cell. Recently, molecular investigations of Ph positive CML cases have revealed a consistent genomic recombination between two genes, BCR on chromosome 22 and the ABL oncogene. The latter is translocated from 9q34, its normal site, to the 22q- or Ph chromosome. This molecular rearrangement expresses a unique 8.5 kb BCR-ABL hybrid mRNA transcript, that encodes an altered BCR-ABL protein of approximately 210 kD with enhanced in vitro tyrosine kinase activity. The breakpoints on chromosome 22q- are clustered in a 5 kb DNA fragment, allowing their study using Southern blot analysis. Cytogenetic variant forms of the Ph translocation involving three or more chromosomes are found in about 5% of the cases. Southern blot and in situ hybridization studies have demonstrated that these variants are cytogenetically more complex than the standard t(9;22) but molecularly they show the same essential genomic recombination. This is also true for a small number of cases of Ph negative CML. Clonal progression, indicated by the presence of clonal, non-random chromosome abnormalities, in addition to the Ph is rare during chronic phase but is found in 80% of blast crisis. These additional aberrations may precede BC by weeks or months and have therefore a clear prognostic value. Ph is not restricted to CML, since it is also found in ALL (20% of adult cases) and rarely in AML. Ph in acute leukaemia is cytogenetically indistinguishable from Ph in CML, but molecular studies have shown that in 50% of the cases the breakpoint on chromosome 22 is different from the very consistent and characteristic breakpoint in CML. Nevertheless genomic recombination takes place that results in a novel ABL protein at least in some of the cases. Despite extensive cytogenetic and molecular investigations, the mechanisms underlying the formation of the Ph as well as the pathogenesis of Ph positive CML are still unknown but are now the object of intensive research.
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PMID:Chromosome abnormalities in CML. 333 58

A DNA region on chromosome 22, designated M-BCR, contains the chromosomal breakpoint of the Philadelphia (Ph) translocation in all Ph positive CML patients studied to date. M-BCR is part of a gene, BCR, oriented with its 5' end towards the centromere of chromosome 22. All of the CML DNAs analysed have a breakpoint within introns of the BCR gene. As a consequence of the Ph translocation the 3' end of the BCR gene has been translocated to chromosome 9, while the 5' part remains on the Ph chromosome. The remaining BCR sequences act as an acceptor for a chromosome 9 gene, the ABL oncogene: the ABL oncogene is fused in a head-to-tail fashion to the chromosome 22 sequences. This genomic configuration results in the transcription of a novel chimeric mRNA consisting of 5' BCR sequences and 3' ABL oncogene sequences. In K562, a cell line derived from a CML patient, and in five CML patients such chimeric BCR/ABL transcripts have been demonstrated. An abnormally sized ABL protein has been detected in the cell line K562 and in leukaemic cells from patients. This protein represents the translational product of the chimeric mRNA. The role of the BCR part of the fusion protein is unknown; it is possible that the BCR moiety could alter the structure of the ABL protein and unmask its tyrosine kinase activity. By analogy with the gag/v-abl polyprotein, the CML-specific BCR/ABL protein might have transforming activity and could play an essential role in the generation and/or maintenance of CML.
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PMID:The BCR/ABL hybrid gene. 333 59

The Philadelphia chromosome (Ph1) is a translocation between chromosomes 9 and 22 that is found in chronic myelogenous leukemia (CML) and a subset of acute lymphocytic leukemia patients (ALL). In CML, this results in the expression of a chimeric 8.5-kilobase BCR-ABL transcript that encodes the P210BCR-ABL tyrosine kinase. The Ph1 chromosome in ALL expresses a distinct ABL-derived 7-kilobase messenger RNA that encodes the P185ALL-ABL protein. Since the expression of different oncogene products may play a role in the distinctive presentation of Ph1-positive ALL versus CML, it is necessary to understand the molecular basis for the expression of P185ALL-ABL. Both P210BCR-ABL and P185ALL-ABL are recognized by an antiserum directed to BCR determinants in the amino-terminal region of both proteins. Antisera to BCR determinants proximal to the BCR-ABL junction in CML immunoprecipitated P210BCR-ABL but not P185ALL-ABL. Nucleotide sequence analysis of complementary DNA clones made from RNA from the Ph1-positive ALL SUP-B15 cell line, and S1 nuclease protection analysis confirmed the presence of BCR-ABL chimeric transcripts in Ph1-positive ALL cells. In Ph1-positive ALL, ABL sequences were joined to BCR sequences approximately 1.5 kilobases 5' of the CML junction. P185ALL-ABL represents the product of a BCR-ABL fusion gene in Ph1-positive ALL that is distinct from the BCR-ABL fusion gene of CML.
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PMID:Expression of a distinctive BCR-ABL oncogene in Ph1-positive acute lymphocytic leukemia (ALL). 342 16

Chronic myelogenous leukaemia (CML) is a clonal disease arising from malignant transformation of pluripotent hematopoietic stem cells. In most cases, it is characterized by the presence of the Philadelphia (Ph1) chromosome (22q-) which results from a reciprocal translocation between chromosomes 9 and 22 (refs 1-3). In this translocation, the human homologue of the Abelson virus oncogene, c-abl, normally on chromosome 9, is moved to chromosome 22, while c-sis, the cellular homologue of the simian sarcoma virus oncogene, is moved from chromosome 22 to chromosome 9 (refs 4-6). CML cells carrying the t(9;22) chromosomal translocation are known to produce an 8-kilobase (kb) c-abl transcript in addition to the normal 6- and 7-kb transcripts and to express the normal p145 abl protein and a p210 c-abl protein possessing a tyrosine kinase activity not detected in the p145 species. Results of our analyses using somatic cell hybrids between a mouse fibroblast line and two human CML-derived cell lines which carry the Ph1 chromosome and are phenotypically identical to the fibroblast parent indicate that only the hybrid cells containing Ph1 chromosome express both the 8-kb c-abl RNA and the p210 protein. Thus, expression of the altered c-abl transcripts and protein depends on the presence of the Ph1 chromosome and is not myeloid-specific.
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PMID:Expression of a translocated c-abl gene in hybrids of mouse fibroblasts and chronic myelogenous leukaemia cells. 345 50

Tyrosine kinase activity is associated with the transforming potential of several oncogenes. Human chronic myeloid leukemia (CML) cells and cell lines have been shown to contain an active bcr-c-abl p210 tyrosine kinase as a consequence of the Philadelphia chromosomal translocation. In the present work the activity of the c-abl and c-src oncogene-encoded tyrosine kinase was investigated during phorbol diester (TPA) induced differentiation of the K562 CML cells. The high tyrosine kinase activity of p210bcr-c-abl is strongly reduced during the initial 24 h of TPA treatment. In contrast, the activity of the c-src tyrosine kinase is not changed. No change occurs in the expression of the c-abl-specific RNAs during this period. Following the reduction of bcr-c-abl kinase activity, cell proliferation is arrested and megakaryoblastic antigens appear on the cells. Sodium butyrate caused a slight decrease in growth rate and of bcr-c-abl kinase activity during erythroid differentiation whereas no changes in c-src or c-abl tyrosine kinase activities were seen in DMSO-treated control cells.
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PMID:The bcr-c-abl tyrosine kinase activity is extinguished by TPA in K562 leukemia cells. 347 72

In chronic myelogenous leukemia (CML) the reciprocal translocation resulting in the Philadelphia chromosome (Ph1) leads to the formation of a chimeric transcriptional unit carrying both c-abl and bcr genetic information whose transcript is a new fused mRNA of 8.5-kilobases (kb) and whose translational product is a 210-kD phosphoprotein with tyrosine kinase activity implicated in the pathogenesis of CML. Twenty patients affected by Ph1-positive CML were studied by Southern blot analysis with bcr. Unexpectedly, in three Ph1-positive patients, the breakpoint of chromosome 22 was located neither inside the bcr region nor 5' to it. Northern blot analysis of the RNAs of two of these patients showed the absence of a detectable 8.5-kb chimeric mRNA. In the third patient a chimeric mRNA was detected by a c-abl cDNA probe but failed to hybridize with a bcr cDNA probe and showed very low hybridization levels with further 5' bcr cDNA probes. The possibility is raised that in CML a breakpoint outside bcr might either still allow the formation of a chimeric mRNA, possibly through alternative splicing mechanisms, or might prevent the transcription of the chimera. In the latter case different molecular events resulting in the formation of a Ph1 chromosome may underlie the same myeloid neoplastic phenotype.
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PMID:Philadelphia-positive chronic myeloid leukemia with a chromosome 22 breakpoint outside the breakpoint cluster region. 347 5

Cytogenic changes are becoming increasingly important in understanding the pathogenesis of human malignancies. The t(9;22) (q34;q11) translocation is one of the most consistent and generates the Philadelphia chromosome (Ph1) (ref. 1) in chronic myeloid leukaemia (CML); it has also been observed in some acute lymphoblastic leukaemias (ALL) (ref. 2). In CML the breakpoints occur on chromosome 22 in the region designated bcr (ref. 3) and result in the expression of a bcr-abl fusion product of relative molecular mass (MT) 210,000 (210K) with associated in vitro tyrosine kinase activity (P210bcr-abl). In some cases of Ph1-positive ALL, a novel abl-related protein (P190all-abl) of 190K has been shown to have tyrosine kinase activity. In this report we demonstrate that the P190all-abl protein has a bcr determinant from the amino-terminal region, but is lacking a bcr determinant normally found in the P210bcr-abl near the bcr-abl junction. The chimaeric nature of the P190all-abl was confirmed by sequential immunoprecipitation with antisera against abl and bcr peptides.
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PMID:Novel chimaeric protein expressed in Philadelphia positive acute lymphoblastic leukaemia. 347 95


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