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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 leukemia (CML) is associated with the reciprocal translocation of a region of chromosome 22 called BCR with the c-abl gene of chromosome 9.5' coding sequences from the BCR gene are spliced in-frame to the second exon of the ABL gene to produce a CML-specific 8.5 kilobase message which encodes the BCR-ABL hybrid protein P210. To definitively identify and characterize the normal BCR gene product, sequences from BCR cDNA clones were used to reconstitute the coding portion of the normal message in retroviral and bacterial transcription vectors. The normal BCR gene product was demonstrated to be a phosphoprotein of 160 kilodaltons by in vitro translation and immunoprecipitation from lysates of NIH3T3 lines expressing BCR retroviruses. Whereas BCR-homologous RNA levels in these cell lines were increased 50 fold, BCR protein levels increased only 2 to 10 fold depending on the presence or absence of BCR-specific 5' and 3' untranslated regions. We observe a kinase activity associated with this protein but we do not observe morphological transformation of NIH3T3 cells as a result of its overproduction.
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PMID:Structural characterization of the BCR gene product. 265 72

Continual monitoring of the presence of the Philadelphia (Ph) chromosome in patients with chronic myelogenous leukemia (CML) is important for diagnosis as well as evaluation of therapy response of these patients. Because the Ph chromosome has been characterized molecularly to involve a reciprocal translocation between the ABL and BCR genes, there is an increasing interest in the use of molecular probes to detect chromosomal rearrangements in this disease. While rearrangements involving the bcr region of the BCR gene can be detected by conventional gel electrophoresis (CGE), detection of those involving ABL generally requires pulsed-field gel electrophoresis (PFGE). Currently, however, CGE and PFGE require different methods of cell preparation, with isolated DNA used in CGE and gel inserts containing whole cells used in PFGE. In this study, we show that the gel-insert method of DNA preparation can be adapted for use in CGE with slight modification of the gel-running conditions. The advantages of this method are demonstrated by studying both bcr and ABL rearrangements in bone marrow and peripheral blood samples of CML patients. Furthermore, we report a novel finding that chromosomal breakpoints in the ABL gene of CML patients occur predominantly between exons 1b and 1a.
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PMID:Studies of BCR and ABL gene rearrangements in chronic myelogenous leukemia patients by conventional and pulsed-field gel electrophoresis using gel inserts. 267 42

The Philadelphia (Ph) chromosome is a small chromosome 22, which results from a reciprocal translocation between the long arms of chromosome 9 and 22, designated t (9;22) (q34;q11). It was first described in association with chronic myeloid leukaemia (CML), where 90% of cases examined are Ph-positive. A similar cytogenetic abnormality has also been identified in the acute leukaemias but in a much lower percentage. The ubiquitous nature of the translocation in CML suggested that it was causally implicated in the pathogenesis of the disease. Recent work at the molecular level has corroborated this idea. As a consequence of the translocation, the Abelson protooncogene (ABL), located on chromosome 9 is moved to chromosome 22 where it is joined to a truncated gene, known as BCR. The result of this genomic reorganisation is a hybrid gene encoding a novel chimaeric protein product with enhanced protein tyrosine kinase activity. It is thought that it is this activity which is necessary for the generation of the leukaemic phenotype. The t(9;22) has provided a model to illustrate how cellular proto-oncogenes can be activated by chromosomal translocation and has stimulated interest in investigating other chromosomal translocations in human malignancies.
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PMID:Molecular biology of the Philadelphia positive leukaemias. 269 Feb 17

A patient whose leukaemic cells carried the rare t(7;11)(p15;p15) was diagnosed as having acute myelomonocytic leukaemia (AML-M4), and supports the association of this specific translocation with forms of acute myeloid leukaemia showing differentiation. Blast phase chronic myeloid leukaemia was excluded by lack of involvement of the ABL and BCR genes. Chromosome in situ hybridization studies showed that both the HRAS1 and INS genes were present on the terminal part of chromosome 11p which was translocated to chromosome 7p. Neither HRAS1 nor INS were structurally rearranged. Field inversion gel electrophoresis showed that a 400 kb fragment encompassing HRAS1 was structurally entire in leukaemic DNA. Because the INS gene, which was also translocated, is probably located proximal to HRAS1 on chromosome 11p, it is unlikely that HRAS1 was near the chromosome 11 breakpoint or involved in this leukaemia.
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PMID:HRAS1 and INS genes are relocated but not structurally altered as a result of the t(7;11)(p15;p15) in a clone from a patient with acute myeloid leukaemia (M4). 271 71

The tyrosine kinase P210 is the gene product of the rearranged BCR-ABL locus on the Philadelphia chromosome (Ph1), which is found in leukemic cells of patients with chronic myelogenous leukemia. It has a weakly oncogenic effect in immature murine hematopoietic cells and does not transform NIH 3T3 cells. We have found that P210 has a strikingly different effect in Rat-1 cells, another line of established rodent fibroblasts. Stable expression of P210 in Rat-1 cells caused a distinct morphological change and conferred both tumorigenicity and capacity for anchorage-independent growth. The introduction of v-myc into Rat-1 cells expressing P210 led to complete morphological transformation and enhanced tumorigenicity. No such interaction took place in NIH 3T3 cells. Thus, Rat-1 cells can be used to detect cooperation between BCR-ABL and other oncogenes and may prove useful for the identification of secondary oncogenic events in chronic myelogenous leukemia.
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PMID:The BCR-ABL oncogene transforms Rat-1 cells and cooperates with v-myc. 272 97

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

Most data suggest that malignant transformation in chronic myelogenous leukemia (CML) occurs in hematopoietic stem cell that is the progenitor of myelopoiesis and of B but not T lymphopoiesis. We established a T-lymphoid cell line (CML-T1) from a person with Ph-chromosome-negative CML in acute phase. Evidence of its T-lymphocyte origin includes the pattern cytochemical reactivity, reactivity with anti-T-cell monoclonal antibodies (MoAbs), and rearrangement of the beta-T-cell receptor (TCRB) gene. CML-T1 cells have features of type IV thymocytes. Cytogenetic analyses indicate a 47,XX, del(11), t(6;7)(q23;q24), +mar karyotype. CML-T1 cells exhibit molecular changes typical of CML, including translocation of the ABL protooncogene from chromosome 9 to 22, rearrangement of the BCR gene, and transcription of a chimeric BCR-ABL messenger RNA (mRNA). The ABL insertion on chromosome 22 appears interstitial, similar to other cases of Ph-chromosome-negative CML. These data clearly indicate that T cells can be involved in acute-phase CML. CML-T1 should be useful in studying this process as well as that underlying Ph-chromosome-negative CML.
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PMID:CML-T1: a cell line derived from T-lymphocyte acute phase of chronic myelogenous leukemia. 278 68

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.
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PMID:The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants. 279 Jul 50

Out of 105 Philadelphia (Ph) positive chronic myeloid leukemia patients analyzed, six (5.7%) carried a variant Ph translocation, namely t(6;9;9;10;22)(q24;p13;q34;p15;q11); t(9;13;22)(q34;q21;q11);der(2)(2pter----2q31::9q21---- 9q34::22q11----22qter) and der(9)t(2;9) (9pter----9q21::2q31----2qter);t(7;9;22)(q11;q34 ;q11), 14q + ;t(7;9;22)(q35;q34;q11), and t(9;11;22) (q34;q13;q11), respectively. Five of these patients were analyzed with Southern blotting. Three of them showed an atypical molecular pattern; namely, the patient with t(9;13;22) showed no rearrangement in the breakpoint cluster region (bcr), the patient with t(7;9;22)(q35;q34;q11) showed a 3' deletion, and the patient with t(7;9;22), 14q + showed a bcr rearrangement 3' to the exon 4 of the M-BCR. Chromosome in situ hybridization studies demonstrated that in patient one, a two-step translocation occurred: the first step moved the 3' bcr from chromosome 22 to chromosome 9, and the second moved the terminal part of 22q, carrying the c-sis protooncogene, to 10p. Variant Ph translocations appear to be associated with atypical molecular breakpoints.
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PMID:Cytogenetic and molecular studies in patients with chronic myeloid leukemia and variant Philadelphia translocations. 279 Jul 54

Philadelphia chromosome-positive acute lymphoblastic leukemia occurs in two molecular forms, those with and those without rearrangement of the breakpoint cluster region on chromosome 22. The molecular abnormality in the former group is similar to that found in chronic myelogenous leukemia. To characterize the abnormality in the breakpoint cluster region-unrearranged form, we have mapped a 9;22 translocation from the Philadelphia chromosome-positive acute lymphoblastic leukemia cell line SUP-B13 by using pulsed-field gel electrophoresis and have cloned the DNA at the translocation junctions. We demonstrate a BCR-ABL fusion gene on the Philadelphia chromosome. The breakpoint on chromosome 9 is within ABL between exons Ia and II, and the breakpoint on chromosome 22 is approximately equal to 50 kilobases upstream of a breakpoint cluster region in an intron of the BCR gene. This upstream BCR breakpoint leads to inclusion of fewer BCR sequences in the fusion gene, compared with the BCR-ABL fusion gene of chronic myelogenous leukemia. Consequently, the associated mRNA and protein are smaller. The exons from ABL are the same. Analysis of leukemic cells from four other patients with breakpoint cluster region-unrearranged Philadelphia chromosome-positive acute lymphoblastic leukemia revealed a rearrangement on chromosome 22 close to the breakpoint in SUP-B13 in only one patient. These data indicate that breakpoints do not cluster tightly in this region but are scattered, possibly in a large intron. Given the large size of BCR and the heterogeneity in breakpoint location, detection of BCR rearrangement by standard Southern blot analysis is difficult. Pulsed-field gel electrophoresis should allow detection at the DNA level in every patient and thus will permit clinical correlation of the breakpoint location with prognosis.
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PMID:Heterogeneity of genomic fusion of BCR and ABL in Philadelphia chromosome-positive acute lymphoblastic leukemia. 283 55


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