bcr-abl RNA in patients with chronic myelogenous leukemia

Shtivelman, Emma; Rp, Gale; Dreazen, O; Berrebi, A; Zaizov, Rina; Kubonishi, Ichiro; Miyoshi, Isao; Canaani, Eli

doi:10.1182/blood.v69.3.971.971

Cited by 85 publications

(10 citation statements)

References 8 publications

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“…Usually, the BCR exon 5' of the breakpoint will be spliced to the closest ABL exon possessing a splice acceptor site: ABL exon 11. However, using the RNase protection assay, we have previously shown that a significant proportion of CMLs contain two BCR-ABL RNA junctions (Shtivelman et al, 1986(Shtivelman et al, , 1987. We interpreted this result as alternative splicing of ABL exon I1 to bcr exons 2 and 3.…”

Section: Introductionmentioning

confidence: 91%

Analysis of BCR‐ABL mRNA in chronic myelogenous leukemia patients and identification of a new BCR‐related sequence in human DNA

Marcelle

Gale

Prokocimer

et al. 1989

Genes Chromosomes & Cancer

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The Philadelphia chromosome is present in more than 95% of chronic myelogenous leukemia patients and in up to 25% of patients with acute lymphocytic leukemia. The major consequence of the aberration is the fusion of the ABL and BCR genes. The position of the breakpoint on chromosome 22 determines which species of the potential three fused mRNAs and proteins will be synthesized. We have used the polymerase chain reaction (PCR) to detect these mRNAs in 53 patients and cell lines and found that around 20% contain simultaneously two BCR-ABL mRNAs, presumably due to a process of alternative splicing. The results also indicate that most patients in lymphocytic blast crisis of CML contain the mRNA in which bcr exon 2 is linked to ABL exon II. Finally, we identified, cloned, and characterized a BCR-related sequence that originated from mRNA.

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Section: Introductionmentioning

confidence: 91%

Analysis of BCR‐ABL mRNA in chronic myelogenous leukemia patients and identification of a new BCR‐related sequence in human DNA

Marcelle

Gale

Prokocimer

et al. 1989

Genes Chromosomes & Cancer

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“…Since the tyrosine kinase activity of the Abelson murine leukemia virus product, p160v-abl, was known to be necessary for cellular transformation, 177 it was proposed soon after its discovery that the constitutive tyrosine kinase activity of p210 bcr-abl may have a crucial role in the pathogenesis of CML, 22,[204][205][206] and there is now abundant evidence confirming the pivotal role of tyrosine phosphorylation in leukemogenesis. [145][146][147]149,153,156,159,160,196,207 The breakpoints for the related Bcr-Abl gene encoding the p190 bcr-abl protein (also referred to as p185 bcr-abl ), found in Ph+ acute leukemias are located in a 20 kb region (known as minor bcr) at the 3 0 end of the first Bcr intron so that the first exon of the Bcr gene (e1) is joined directly to the second Abl exon, resulting in an e1a2 fusion in p190 bcr-abl .…”

Section: Human Leukemias Caused By Bcr-abl Oncogenesmentioning

confidence: 99%

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

et al. 2003

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The chronological history of the important discoveries leading to our present understanding of the essential clinical, biological, biochemical, and molecular features of chronic myelogenous leukemia (CML) are first reviewed, focusing in particular on abnormalities that are responsible for the massive myeloid expansion. CML is an excellent target for the development of selective treatment because of its highly consistent genetic abnormality and qualitatively different fusion gene product, p210(bcr-abl). It is likely that the multiple signaling pathways dysregulated by p210(bcr-abl) are sufficient to explain all the initial manifestations of the chronic phase of the disease, although understanding of the circuitry is still very incomplete. Evidence is presented that the signaling pathways that are constitutively activated in CML stem cells and primitive progenitors cooperate with cytokines to increase the proportion of stem cells that are activated and thereby increase recruitment into the committed progenitor cell pool, and that this increased activation is probably the primary cause of the massive myeloid expansion in CML. The cooperative interactions between Bcr-Abl and cytokine-activated pathways interfere with the synergistic interactions between multiple cytokines that are normally required for the activation of stem cells, while at the same time causing numerous subtle biochemical and functional abnormalities in the later progenitors and precursor cells. The committed CML progenitors have discordant maturation and reduced proliferative capacity compared to normal committed progenitors, and like them, are destined to die after a limited number of divisions. Thus, the primary goal of any curative strategy must be to eliminate all Philadelphia positive (Ph+) primitive cells that are capable of symmetric division and thereby able to expand the Ph+ stem cell pool and recreate the disease. Several highly potent and moderately selective inhibitors of Bcr-Abl kinase have recently been discovered that are capable of killing the majority of actively proliferating early CML progenitors with minimal effects on normal progenitors. However, like their normal counterparts, most of the CML primitive stem cells are quiescent at any given time and are relatively invulnerable to the Bcr-Abl kinase inhibitors as well as other drugs. We propose that survival of dormant Ph+ stem cells may be the most important reason for the inability to cure the disease during initial treatment, while resistance to the inhibitors and other drugs becomes increasingly important later. An outline of a possible curative strategy is presented that attempts to take advantage of the subtle differences in the proliferative behavior of normal and Ph+ stem cells and the newly discovered selective inhibitors of Bcr-Abl. Leukemia (2003) 17, 1211-1262. doi:10.1038/sj.leu.2402912

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“…In CML this translocation fuses the second exon of the abl gene (a2) into the central portion of the bcr gene. Most frequently a2 is fused to one of 2 small exons in the major breakpoint cluster region of the bcr gene, termed b2 and b3 (4). Following transcription and alternative splicing (5) both gene fusions generate mRNA encoding for a bcr-abl protein of more than 2000 amino acids (p210) (6) with increased tyrosine kinase activity (7).…”

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confidence: 99%

Bcr‐abl protein detection in peripheral blood mononuclear cells for follow‐up of chronic myelogenous leukaemia patients

Schleuning

Mittermüller

Kölb

1999

European J of Haematology

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We have assessed the value of p210 protein detection in peripheral blood cells for follow‐up of chronic myelogenous leukaemia (CML) patients. Quantification was achieved by comparing the relative intensities of the p210 bands with those of the normal abl protein (p145). Serial dilution of Ph‐positive K562 cells with Ph‐negative HL60 or KG1 cells revealed a linear correlation between the p210/p145 ratio and the number of Ph‐positive cells (r = 0.998; p < 0.001) with a sensitivity of detecting less than 1% Ph‐positive cells in 5 times 106 cells. Ninety‐six consecutive patients were enrolled in the study and a total of 155 Western blot analyses have been performed and compared to chromosomal analyses of bone marrow. Parallel RT–PCR analyses have been performed on 99 occasions. All patients with positive cytogenetic findings also probed positive for p210. In 23 instances p210 was detectable despite negative chromosomal analysis. In 16 samples these results were confirmed by RT–PCR. In patients with partial cytogenetic remission (n = 26) the results of the p210 assay correlated significantly with the percentage of Ph‐positive metaphases (r = 0.69; p < 0.001). In conclusion, monitoring of CML patients by quantification of the bcr‐abl protein is a feasible and sensitive alternative to chromosomal analysis of bone marrow.

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bcr-abl RNA in patients with chronic myelogenous leukemia

Cited by 85 publications

References 8 publications

Analysis of BCR‐ABL mRNA in chronic myelogenous leukemia patients and identification of a new BCR‐related sequence in human DNA

Analysis of BCR‐ABL mRNA in chronic myelogenous leukemia patients and identification of a new BCR‐related sequence in human DNA

Chronic myelogenous leukemia as a paradigm of early cancer and possible curative strategies

Bcr‐abl protein detection in peripheral blood mononuclear cells for follow‐up of chronic myelogenous leukaemia patients

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