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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 translocation, which is present in 90-95% of chronic myelogenous leukemia patients, involves translocation of the c-abl protooncogene to chromosome 22 and is accompanied by activation of embryonic globin gene expression in the K562 chronic myelogenous leukemia cell line. To test directly if the protein products of the translocated c-abl protooncogene can activate embryonic globin gene expression, we transfected the v-abl oncogene (which shares the property of autophosphorylation with the translocated c-abl protooncogene) into mouse erythroleukemia cells. v-abl-transfected mouse erythroleukemia cells, which contained multiple copies of the v-abl transgenome, exhibited activation of mouse embryonic globin gene expression. These results suggest that the translocated c-abl protooncogene of the Philadelphia chromosome translocation is central to the pathogenesis of chronic myelogenous leukemia and that it may result in the activation of embryonic globin genes in some chronic myelogenous leukemia cell lines.
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PMID:v-abl activates embryonic globin gene expression in mouse erythroleukemia cells. 300 48

We surveyed 20 Philadelphia chromosome (Ph1) positive chronic myelogenous leukemia (CML) samples by Southern blot hybridization to determine the location of the breakpoints that occur on chromosomes 9 and 22 in the Ph1 translocation. Only 3 of 20 samples exhibited breakpoints on chromosome 9 within 18 kilobases (kb) of the v-abl homologous sequences. Mapping of these three chromosome 9 breakpoints indicates that each is at a separate location within this 18-kb region, indicating that there are no breakpoint "hot spots" in this area. In contrast, all 20 CML samples exhibited breaks on chromosome 22 within a 5.0-kb Bgl II fragment that lies within the previously described breakpoint cluster region (bcr). Several patients with CML blast crisis exhibiting multiple Ph1 chromosomes/metaphase exhibited amplified and rearranged c-abl-related fragments. These additional Ph1 chromosomes in blast crisis cells do not arise from a second, independent 9:22 translocation but rather result from a duplication of the preexisting Ph1 chromosome.
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PMID:Breakpoints on chromosomes 9 and 22 in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Amplification of rearranged c-abl oncogenes in CML blast crisis. 302 20

The expression of c-abl, c-sis, c-myc and N-ras oncogenes was examined in 2 lymphoblastoid cell lines, one with Ph1 (PB-1049) and the other without Ph1 (LN-1049), both established from a patient with chronic myelogenous leukemia (CML), and in a Ph1-positive cell line (PB-1049-T) derived from a tumor formed after transplantation of PB-1049 cells in a nude mouse with reference to their tumorigenic potential in nude mice. The normal transcripts of c-abl were detected in all 3 lymphoblastoid cell lines. Although in situ hybridization of v-abl proved, and restriction endonuclease analyses of the bcr region strongly indicated the occurrence of bcr-abl rearrangement in PB-1049 and PB-1049-T, we could not obtain any evidence for the expression of the hybrid bcr-abl mRNA. These results indicate that the Ph1 translocation does not ensure the production of the hybrid bcr-abl mRNA, and that the expression of hybrid bcr-abl gene is not essential for the maintenance of tumorigenicity of these cell lines. Expression of c-sis was not detected in any of the cell lines examined, whereas the expression of c-myc was uniformly higher in the 3 cell lines than in normal control cells. The levels of N-ras expression varied considerably, probably in parallel with the changes in tumorigenicity of the cell lines. N-ras expression in the PB-1049 and PB-1049-T cell lines was higher than that in the LN-1049 line when they retained tumorigenic potential, but it fell to the level of LN-1049 with loss or decline of tumorigenicity.
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PMID:Absence of the hybrid bcr-abl mRNA in Ph1-positive B lymphoblastoid cell lines established from a patient with chronic myelogenous leukemia. 312 21

The reciprocal translocation between human chromosomes 9 and 22, termed the Philadelphia chromosome (Ph1), is observed in more than 90% of patients with chronic myelogenous leukemia. This translocation fuses sequences from a variable distance 5' to the c-abl locus on chromosome 9 to sequences in a breakpoint cluster region (bcr) on chromosome 22. The appearance of the Ph1 chromosome is correlated with the production of a novel 8.7-kb RNA transcript containing both bcr and c-abl sequences as well as with a 210-kd phosphoprotein (p210c-abl) representing non-abl polypeptide sequences fused to c-abl-derived sequences. Antibodies prepared to a number of different c-abl domains and to bcr determinants were employed to characterize the normal and altered c-abl gene products. By combining a variety of cDNA cloning techniques, we have isolated bcr/abl clones representing 8.7 kb of contiguous mRNA sequence.
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PMID:Molecular cloning and serological characterization of an altered c-abl gene product produced in Ph1 CML patients. 312 80

The P210bcr/abl protein is associated with virtually every case of human chronic myelogenous leukemia. Unlike the related P160gag/v-abl oncogene product of Abelson murine leukemia virus, P210bcr/abl does not transform NIH 3T3 fibroblasts. To assess whether P210bcr/abl might transform hematopoietic cell types, retroviral constructs encoding P210bcr/abl were used to infect the bone marrow-derived interleukin 3-dependent Ba/F3 cell line. As for P160gag/v-abl, cell lines expressing P210bcr/abl were growth factor independent and tumorigenic in nude mice. No evidence for autocrine production of interleukin 3 by factor-independent cell lines was found. These experiments establish that P210bcr/abl can transform hematopoietic cell types to tumorigenicity.
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PMID:Transformation of an interleukin 3-dependent hematopoietic cell line by the chronic myelogenous leukemia-specific P210bcr/abl protein. 314 16

Activation of the oncogenic potential of c-abl proto-oncogene has been correlated with the activation of its tyrosine kinase activity. The oncogenes derived from c-abl, e.g., gag/v-abl in Abelson murine leukemia virus or bcr/abl in chronic myelogenous leukemia, lack N-terminal coding sequences of the normal c-abl gene. In mouse and human cells, two sets of N-terminal amino acids encoded by 5'-variable exons are found in c-abl proteins. To assess the importance of N-terminal deletion in the activation of c-abl tyrosine kinase, a full length or an N-terminal deleted c-abl protein was expressed in bacteria and in monkey COS cells. Measurements of the autokinase activity of these two c-abl proteins showed that deletion of the N-terminal amino acids led to a three to five fold increase of the c-abl tyrosine kinase activity. Thus, the N-terminal deletion is important in the activation of c-abl proto-oncogene.
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PMID:Negative regulation of c-abl tyrosine kinase by its variable N-terminal amino acids. 314 98

In chronic myeloid leukemia (CML), a chromosome translocation has fused the bcr gene to the c-abl oncogene, such that a chimeric bcr-abl polypeptide can be made. To explore the biological properties of bcr-abl and compare them with those of the Abelson virus (AMuLV) transforming gene (gag-v-abl), we have used either a synthetic bcr-v-abl gene that mimics the translocation product or, in some experiments, a bcr-c-abl cDNA. A new retroviral vector was used to introduce the genes into the factor-dependent myeloid line FDC-P1. Both bcr-abl and v-abl efficiently rendered the myeloid cells factor independent and tumorigenic. Their fully autonomous growth may be due to the myeloid growth factor interleukin-3 (IL-3) made in small amounts by the infected cells. Hence autocrine factor production may feature in CML development and Abelson virus transformation.
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PMID:bcr-abl oncogene renders myeloid cell line factor independent: potential autocrine mechanism in chronic myeloid leukemia. 314 34

The relationship between chronic myelogenous leukemia (CML) with and without the Ph1 chromosome is controversial. Although some suggest that these disorders are identical, other reports suggest that Ph1 chromosome negative CML is a distinct entity. To resolve this issue, we studied 11 patients with Ph1 chromosome negative CML for the translocation of the Abelson proto-oncogene (c-abl) to the breakpoint cluster region gene (bcr), internal genomic rearrangement of bcr, and transcription of a chimeric bcr/abl mRNA. Our data indicate that c-abl is translocated to chromosome 22 where it is inserted after exon "2" or "3" of the bcr gene. This results in transcription of a chimeric bcr/abl mRNA in which the splice is between bcr exon "2" or "3" and c-abl exon 2. These data suggest that CML with and without the Ph1 chromosome are molecularly identical disorders with regard to bcr and abl.
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PMID:The bcr gene is joined to c-abl in Ph1 chromosome negative chronic myelogenous leukemia. 321 10

DNA of peripheral blood or bone marrow leukocytes from 8 normal subjects, 7 cases of acute lymphocytic leukemia (ALL), 2 of acute myelogenous leukemia (AML) and 1 of chronic myelogenous leukemia (CML), having been digested by endonuclease Eco RI or Pst I separately, was hybridized with the probes of 3' fragment (Pst I/Hind III) or 5' fragment (Hinc II/Pst I) of Abelson murine leukemia virus (A-MuLV) oncogene v-abl. The proto-oncogene c-abl, which is homologous to v-abl, was found amplified in 4 ALL, 1 CML and 1 AML. In one of these 4 ALL, c-abl was amplified even over 100 times. A new c-abl BamH I fragment with 6.7 kilobase pairs (kb) in length was observed in 2 ALL and 1 CML out of these 6 cases with amplification, but none of this fragment was found in the normal subjects or other leukemia patients. These 3 patients with the presence of 6.7 kb fragment were high risk ones and 2 of them had died, suggesting that 6.7 kb fragment be the index of poor prognosis. The amplification and rearrangement of c-abl imply the activation of proto-oncogene in leukemogenesis.
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PMID:[Amplification and rearrangement of proto-oncogene c-abl in human leukemia cells]. 321 75

The fundamental pathogenetic significance of the Ph chromosome abnormality in CML has been clarified by molecular studies. However, this balanced reciprocal t(9;22) is probably not the primary event in the pathogenesis of this disease, at least at a cytogenetic level. The cause of Ph variants in +/- 5% of patients is still unknown. Improvements in cytogenetic techniques and molecular studies in a limited number of cases indicate that simple variants do not exist: Region 9q34 appears to be involved in all types of Ph variants. There is tentative evidence that these variants may in fact represent a clonal evolution from a standard t(9;22). The types of additional secondary abnormalities found in Ph variants are the same as those commonly found in standard cases. Ph negative CML represents a heterogeneous group of myeloproliferative/myelodysplastic disorders. The various mechanisms that could lead to Ph negativity are discussed. Some karyotypically normal cases and those showing a chromosome abnormality other than the Ph during the chronic phase have shown the same molecular changes as found in Ph positive CML. The types of clonal changes accompanying transformation to an acute phase are similar to those seen in myeloid disorders as a whole. The prognostic karyotypic factors in predicting imminent metamorphosis to the acute stage and during the acute phase are discussed. The extent of clonal evolution, the type of secondary abnormalities, and their relationship to the hematopoietic lineage of blast cells should be assessed. The nonrandom clonal changes found in 80% of cases are +Ph, +8, i(17q), +19, and loss of the Y. The significance of +Ph is possibly related to amplification of the bcr/abl fusion gene product, but the reason for the other persistent nonrandom changes is still speculative. Recent cytogenetic data indicate that the specific changes observed in various types of ANLL may be seen in corresponding types of MT, such as t(15;17) in promyelocytic transformations and abnormalities of 3q21-3q26 in megakaryoblastic transformations. Patients with LT usually have an early precursor B phenotype associated with a better prognosis. They tend to have either normal or hypodiploid karyotypes. An i(17q) is never seen and +8 and +19 are absent in most series. Duplication of the Ph and loss of the Y are common to both MT and LT. Data relating 14q+ abnormalities to LT are presently ambiguous.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cytogenetics of chronic myelogenous leukemia. 327 13


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