Altered Transcription of an Oncogene in Chronic Myeloid Leukaemia

Canaani, Eli; Steiner-Saltz, D.; Aghai, E; Gale, Robert Peter; Berrebi, A; Januszewicz, E.

doi:10.1016/s0140-6736(84)90997-8

Cited by 145 publications

(29 citation statements)

References 19 publications

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“…An extra band of approximately 11 kb is also visible and may represent c-abl precursor RNA, which has not been studied in further detail. The abnormally sized mRNA seems to be characteristic of Ph'-positive cells, as it is not detected in either normal control cells or cells of other types of leukemia (4,11).…”

Section: Resultsmentioning

confidence: 81%

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript.

Grosveld¹,

Verwoerd²,

Agthoven³

et al. 1986

Mol. Cell. Biol.

162

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In the DNAs of all Ph1-positive chronic myelocytic leukemia patients studied to date, a breakpoint on chromosome 22 (the Ph1 chromosome) can be demonstrated with a probe from the bcr (breakpoint cluster region). Although the K562 cell line was established from cells of a chronic myelocytic leukemia patient, we have been unable to detect the Ph1 chromosome by cytogenetic means. Employing a probe from the 5' region of bcr, we have cloned an amplified Ph1 breakpoint fragment from K562. This demonstrates that K562 contains multiple remnants of a Ph1 chromosome with a breakpoint within bcr and thus may serve as a model system for the study of Ph1-positive chronic myelocytic leukemia at a molecular level. The isolation of bcr cDNA sequences shows that parts of bcr encode a protein. Employing K562, we demonstrate the presence of an abnormally sized mRNA species hybridizing to c-abl and to a bcr cDNA probe, indicating the possible consequence of the Ph1 translocation on a transcriptional level in chronic myelocytic leukemia. The isolation and sequencing of a cDNA containing the breakpoint area of this mRNA provide further evidence for its chimeric structure. Cloning of large stretches of chromosomal DNA flanking bcr and c-abl sequences in K562 and identification of the exons participating in the formation of the chimeric mRNA shows that a splice of at least 99 kilobases is made to fuse the 3' bcr exon to the 5' c-abl exon. Furthermore two chimeric cDNAs were isolated containing chromosome 9 sequences that map 43.5 kilobases downstream from the K562 breakpoint. These chromosome 9 sequences neither hybridize to the 8.5-kilobase chimeric c-abl mRNA nor to normal c-abl mRNAs in Hela cells and probably represent incorrect splicing products present in the K562 cell line.

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Section: Resultsmentioning

confidence: 81%

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript.

Grosveld¹,

Verwoerd²,

Agthoven³

et al. 1986

Mol. Cell. Biol.

162

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“…Karyotypic analysis of cells from patients K and A, both of whom were in blast crisis, revealed the presence of two and three Ph' chromosomes, respectively, per metaphase. In both these cells, the aberrant Bgl II fragment detected by the Hind III-Eco RI 5' abl probe appears to be amplified, since this probe hybridizes more intensely to the rearranged Bgl II fragment than to the germline fragment (Fig. 5, lanes A and K) (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…The normal physiologic function of c-abl is presently unknown although its homologue v-abl is known to have tyrosine kinase activity (4). An abnormally large 8-kb ablrelated RNA transcript has been noted in CML cells (5,6) and this aberrant message appears to be transcribed from the translocated c-abl oncogene on the Ph'. This abnormally large mRNA may code for P210, the abnormal-sized abl-related protein product that has been noted recently in CML cells (7,8).…”

Section: Introductionmentioning

confidence: 99%

Breakpoints on chromosomes 9 and 22 in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Amplification of rearranged c-abl oncogenes in CML blast crisis.

Collins¹

1986

J. Clin. Invest.

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We surveyed 20 Philadelphia chromosome (Ph') positive chronic myelogenous leukemia (CML) samples by Southern blot hybridization to determine the location ofthe breakpoints that occur on chromosomes 9 and 22 in the Ph' 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 Ph' chromosomes/metaphase exhibited amplified and rearranged c-abl-related fragments. These additional Ph' chromosomes in blast crisis cells do not arise from a second, independent 9:22 translocation but rather result from a duplication of the preexisting Ph' chromosome.

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“…Studies of the structure of the leukocyte DNA of cases 4, 5 and 11, using three restriction enzymes (Bam H1, Eco RI and Hind iii) and Southern blot analysis with cDNA probes for the major bcr region (Canaani et al, 1984), were done by our colleague Dr Mark Minden.…”

Section: Methodsmentioning

confidence: 99%

The maintenance of busulphan-induced remissions in chronic granulocytic leukaemia with recombinant interferon α-2b

Bergsagel

Messner²

1990

Br J Cancer

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Altered Transcription of an Oncogene in Chronic Myeloid Leukaemia

Cited by 145 publications

References 19 publications

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript.

The chronic myelocytic cell line K562 contains a breakpoint in bcr and produces a chimeric bcr/c-abl transcript.

Breakpoints on chromosomes 9 and 22 in Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Amplification of rearranged c-abl oncogenes in CML blast crisis.

The maintenance of busulphan-induced remissions in chronic granulocytic leukaemia with recombinant interferon α-2b

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