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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 chromosome (Ph1), detected in virtually all cases of chronic myelogenous leukemia, is formed by a reciprocal translocation between chromosomes 9 and 22 that fuses BCR encoded sequences upstream of exon 2 of c-ABL. This oncogene produces a fusion protein (p210BCR/ABL) in which the ABL tyrosine kinase activity is elevated. This elevated kinase activity is essential for transformation, but the mechanisms involved are unknown. We report here that p21ras GTPase activating protein (rasGAP) or rasGAP-associated proteins p190 and p62 are phosphorylated on tyrosine in Ph1 (+) cell lines. Further, rasGAP coimmunoprecipitates with p210BCR/ABL in these cell lines. These results suggest that rasGAP or associated proteins are potential substrates for p210BCR/ABL kinase and thus directly link p210BCR/ABL with a signal transduction pathway known to be activated by hematopoietic growth factors (p21ras).
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PMID:Tyrosine phosphorylation of rasGAP and associated proteins in chronic myelogenous leukemia cell lines. 157 36

Chromosomal translocation within B and T cell malignancies has proven a rich source for proto-oncogenes. The obligate DNA breaks within immunoglobulin (Ig) and T cell receptor (TCR) loci are frequently the sites of recurrent translocations. Burkitt's lymphoma established the paradigm by introducing the myc oncogene from chromosome segment 8q24 into the Ig heavy chain gene locus at 14q32. Molecular cloning of an aberrant Ig rearrangement in follicular lymphoma revealed Bcl-2. Bcl-2 constitutes the first member of a new category of oncogenes: regulators of programmed cell death. Bcl-2 blocks apoptosis and maintains long-term immune responsiveness including B-cell memory. The PRAD1 gene of parathyroid adenomas appears to be the elusive Bcl-1 gene of t(11;14)(q13;q32) bearing lymphomas. It proves to be a novel G1 cyclin. Acute lymphoblastic leukemias (ALL) pre-B phenotype produce a E2A/PBX fusion protein that possesses the leucine zipper of E2A with the homeodomain of PBX. Two molecular forms of the BCR/ABL fusion protein are produced by the Philadelphia chromosome. A deregulated p210 tyrosine kinase is found in chronic myelogenous leukemia, while a p190 form predominates in Ph+ ALL. In contrast, T-cell ALLs introduce a potpourri of genes into their T cell receptor loci. However, a common theme is emerging. These oncogenes (Ttg1, Ttg2, SCL, LylI, H0X11) all belong to classic families of transcription factors, possessing LIM domains, helix-loop-helix motifs, or homeodomains. Provocatively, these transcription factors are normally intended for lineages other than T cells. These genes have widened the horizons of both oncogenesis and normal development.
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PMID:Chromosomal translocations in lymphoid malignancies reveal novel proto-oncogenes. 159 Oct 3

Two cases are described with the rare combination of inv(16)(p13q22), strongly associated with acute myelomonocytic leukemia with eosinophilia, M4Eo, and the Philadelphia translocation, t(9;22)(q34;q11), hallmark of chronic myeloid leukemia (CML) and rarely found, (less than 1%), in acute nonlymphocytic leukemia. The patients were: case 1, a 9-year-old girl presenting with a white blood cell count (WBC) 42 x 10(9)/L with 32% blasts and bone marrow with blasts and eosinophil precursors consistent with M4Eo, and case 2, a 25-year-old man with WBC 34.7 x 10(9)/L with 13% blasts and bone marrow with features of M4Eo and basophilia. Both patients achieved remission but died following bone marrow transplantation in first remission (case 1) or in relapse (case 2). Cytogenetic findings were: case 1, at diagnosis, 46,XX,inv(16)(p13q22)(21)/46,XX,t(9;22) (q34;q11),inv(16)(8)/46,XX(10), and case 2, at diagnosis, 46,XY,t(9;22) (q34;q11),inv(16)(p13q22) (16) and in remission, 46,XY,t(9;22)(q34;q11) (1)/46,XY (24). Investigation of the breakpoint on 22 in case 1 with Southern blotting and the polymerase chain reaction demonstrated the presence of a p190 mRNA and a breakpoint typical of acute leukemia. Thus a diagnosis of M4Eo was supported by clinical and cytogenetic sequelae in each case; the Ph in case 1 was apparently secondary to inv(16), in case 2 the Ph probably preceded inv(16) in the etiology of the leukemia.
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PMID:Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases. 172 47

The Philadelphia (Ph) translocation is responsible for the generation of the chimeric BCR/ABL oncogene. The Ph chromosome constitutes the earliest detectable chromosome abnormality in chronic myelogenous leukemia and is also found in acute lymphoblastic leukemia. Mice transgenic for a P190 BCR/ABL-producing DNA construct develop lymphoblastic leukemia/lymphoma and provide an opportunity to study early stages of the disease as well as progression. In this study, we have karyotyped the bone marrow of 10 19-day-old BCR/ABL P190 transgenic mice from a line that reproducibly develops leukemia/lymphoma. Leukemic cells from 17 terminally ill transgenic founders and progeny were also karyotyped as well as bone marrow transplant recipients of leukemic donor marrow. Karyotypically visible aberrations were absent from the early stages of BCR/ABL P190-generated leukemia and normal metaphases could be found even in the terminal stages of the disease. A high frequency of aneuploidy was found in advanced leukemia, with a marked preference for the gain of mouse chromosomes 12, 14, or 17. These results point to a primary role for BCR/ABL in leukemogenesis and suggest a destabilizing effect of the BCR/ABL gene on the regulation of cell division.
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PMID:Clonal development and karyotype evolution during leukemogenesis of BCR/ABL transgenic mice. 173 87

Two bcr/abl fusion gene products with tyrosine kinase activity have been found in two phenotypes of Philadelphia chromosome (Ph1)-positive leukemia. P210bcr/abl (P210) is associated with Ph1-positive chronic myelogenous leukemia (CML), while P190bcr/abl is associated with Ph1-positive acute leukemia. We compared the susceptibility of 32Pi-labeled P210 from K-562 cells and P190 from MR-87 cells to protein tyrosine phosphatase (PTPase). PTPase, present in the lysate of mature granulocytes from CML patients as well as in the lysate of these cells from normal subjects, effectively dephosphorylated the CML-associated P210 and the acute leukemia associated P190. This PTPase activity was specifically inhibited by ZnCl2; it was not present in lymphocyte lysates, and was not inhibited by neutralization with anti-CD45 antibody. Since P210 and P190 were equally sensitive to the PTPase, the difference in leukemic phenotypes associated with the expression of these two tyrosine kinases cannot be explained by the differential dephosphorylation of P210 and P190.
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PMID:Two bcr/abl fusion gene products, P210bcr/abl and P190bcr/abl, are equally sensitive to the protein tyrosine phosphatase of mature granulocytes. 179 29

We investigated the significance of p210 and p190 molecular abnormalities in 32 adults with Philadelphia chromosome (Ph)-positive acute leukemia. p210 was detected in 15 patients (47%), p190 in 16 (50%), and both in one (3%). p210 was noted in 11 of 24 patients (46%) with acute lymphocytic leukemia, and in four of eight patients (50%) with acute myelogenous or undifferentiated leukemia. Among 29 patients with untreated disease (p210, 14 patients; p190, 15 patients), no significant differences in the two molecularly distinct groups were observed by pretreatment characteristics including age, degree of organomegaly, anemia, leukocytosis, thrombocytopenia, occurrence of karyotypic abnormalities in addition to Ph, or residual diploid metaphases. Complete response (CR) rates were also similar. Although the remission duration tended to be longer with p190 (P = .08), the differences were minor (median duration 29 v 20 weeks) and not paralleled by differences in survival rate. In 10 patients studied by karyotypic analysis in remission, two of four patients with p190 and two of six patients with p210 showed 100% normal metaphases. One of the seven patients (14%) with p210 who achieved CR manifested a morphologic picture of second chronic-phase chronic myelogenous leukemia lasting for 1 month. We conclude that the molecular studies in Ph-positive acute leukemia are not associated with significantly different clinico-laboratory, karyotypic, or prognostic implications.
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PMID:Significance of the P210 versus P190 molecular abnormalities in adults with Philadelphia chromosome-positive acute leukemia. 193 53

The Philadelphia translocation in chronic myelogenous leukemia (CML) results in the production of a 210 kD BCR-ABL protein. In contrast, in 50% of Philadelphia-positive acute leukemias, the translocation results in the production of a 190 kD BCR-ABL protein. To investigate the hypothesis that the production of P190 may be associated with the progression from chronic phase to blast crisis in CML, we used polymerase chain reaction to analyze blood from 37 patients with accelerated phase/blast crisis CML for the transcripts coding for the P210BCR-ABL and P190BCR-ABL. The mRNA encoding for P210 was detected in all patients. In three patients, mRNA encoding both P210 and P190 was present. In two of these three patients, samples were available from the time of initial diagnosis. Analysis of these samples did not reveal any transcripts for P190. We conclude that in some patients the appearance of P190BCR-ABL may correlate with transformation to a more aggressive, terminal phase of CML.
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PMID:Appearance of acute leukemia-associated P190BCR-ABL in chronic myelogenous leukemia may correlate with disease progression. 201 78

Three major types of mRNA can be expressed as a result of the Philadelphia translocation, dependent on the position of the break within the BCR gene on chromosome 22. In addition, alternative splicing of the mRNA transcribed from the BCR/ABL fusion gene has been reported and it has been suggested that this may play a role in the generation of the acute phase of Philadelphia positive chronic myeloid leukaemia (CML). We have examined the fusion RNA present in 24 cases of chronic phase CML and 21 cases of patients with CML in blast crisis using the polymerase chain reaction. In no case was it possible to detect the presence of the e1a2 junction which encodes the p190 hybrid protein product. We conclude that the acquisition of the p190 does not play a significant role in the generation of the blast crisis of CML. Neither could we detect a significant difference in the number of cases which simultaneously express both b2a2 and b3a2 junction products in samples isolated from chronic phase and blast crisis. In the series analysed by ethidium bromide stained gels, there was, however, an increase in the percentage of cases expressing the b3a2 junction in the mononuclear cells of blast crisis patients as compared to the white blood cells of patients in chronic phase.
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PMID:The role of alternative splicing patterns of BCR/ABL transcripts in the generation of the blast crisis of chronic myeloid leukaemia. 222 46

The presence of Philadelphia chromosome t(9:22) is a hallmark of 95% of clinical cases of chronic myelogenous leukemia (CML) as well as 20% of adult acute lymphoblastic leukemia (ALL) and 5% of acute myeloid leukemia (AML). The product of t(9;22) is a fusion protein BCR-ABL. The fusion proteins of CML, ALL and AML have increased tyrosine kinase activity and show a transforming potential in vitro and in animal models. The shorter p190 protein is associated almost only with ALL and AML, while the protein p210 is present in both chronic phase and blast crisis of CML and also in 50% of Philadelphia-positive (Ph1+) ALL. In CML the transition from chronic phase to blast crisis is usually accompanied by additional genetic events, e.g. additional chromosomal abnormalities, and oncogene activation(s). The detailed understanding of molecular basis of CML, and Ph1+ ALL and AML provides highly sensitive molecular and serological methods to complement classical cytogenetics. The advantages and limitations of these techniques are described and discussed below.
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PMID:Molecular pathology of chronic myelogenous leukemia. 224 53

The diagnosis and classification of leukaemia started with simple morphological examination and now embraces use of special stains, cytochemistry and immunophenotyping. Genetic studies have progressed from karyotyping to detection of genetic changes within genes. The methods described in this chapter are still at an early stage of development and, so far, have provided relatively little in the way of an extension of available diagnostic information. Sometimes the methods provide extensions to existing techniques, for example by the detection of bcr rearrangements in patients who have CML or ALL but do not have a detectable Philadelphia chromosome. Another example is retrospective diagnosis of gene rearrangements using DNA from slide preparations. However, it should be noted that it has only very recently been shown that there is likely to be a causal relationship between the Ph chromosome and leukaemia. Daley et al (1990) induced CML in mice by bone marrow transplantation of cells infected with a retrovirus encoding P210bcr/abl and Heisterkamp et al (1990) produced mice transgenic for a BCR/ABL P190 DNA construct and showed that the progeny died of acute leukaemia (mostly ALL). We have not summarized studies of the incidence of activated oncogenes such as RAS in leukaemia and myelodysplasia. Such oncogenes appear to be involved in many tumours and may well indicate either a predisposition to cancer or a particular stage of malignancy, but their analysis does not at present help in making a diagnosis. It is likely that, as we understand more about the nature of the malignant process, we shall be able to use genetic techniques to enhance considerably both diagnostic and prognostic precision.
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PMID:Molecular biology and leukaemia diagnosis. 227 97


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