Breakpoint cluster region

In chronic myelogenous leukemia (CML) as well as in a subset of acute lymphoblastic leukemia (ALL) Bcr-Abl, a fusion protein of c-Abl and the breakpoint cluster region (bcr), is expressed in the cytosol of leukemic cells. This fusion protein forms homo-oligomeric complexes that display elevated kinase activity and is the causative molecular abnormality in CML and certain ALL. The transforming effect of Bcr-Abl is mediated by numerous downstream signaling pathways, including protein kinase C (PKC), Ras-Raf-ERK MAPK, JAK-STAT (see below), and PI3-kinase pathways. 

A well-known use of molecular methods is in the study of chromosomal translocations. Thus, in Philadelphia chromosome (ph1) positive chronic myelogenous leukemia (CML), the C-abl oncogene on chromosome 9 is translocated to a region on chromosome 22 called the breakpoint cluster region, or bcr. This (t9 22) translocation results in production of an abnormal fusion protein... 

Schmidt HH, Strehl S, Thaler D, Strunk D, Sill H, Linkesch W, Jager U, Sperr W, Greinix HT, Konig M, Emberger W, Haas O A (2004) RT-PCR and FISH analysis of acute myeloid leukemia with t(8 16)(p 1 l p 13) and chimeric MOZ and CBP transcripts breakpoint cluster region and clinical implications. Leukemia 18 1115—1121... 

Breakpoint cluster region-Abelson leukemia virus tyrosine kinase Twice a day... 

The translocation moves the c-ABL gene that encodes a tyrosine kinase from chromosome 9 to the breakpoint cluster region fBCRj of chromosome 22. 

Fig. 3. A simplified illustration of BCR-ABL and SRC family kinase involvement in oncogenic signaling pathways. The inhibitory effect is indicated by the upside-down T s. ABL = Abelson tyrosine kinase BCR = breakpoint cluster region FAK = focal adhesion kinase Grb-2 = growth factor receptor-bound protein 2 HcK = hematopoietic cell kinase JNK = Jun amino-terminal kinase P = phosphate group PI3 K = phosphatidylinositol-3-kinase SFK = SRC family kinases StatS = signal transducer and activator of transcription 5. (Reprinted with permission from Ref (123)). 

Figure 3. The human BCR gene consists of 23 exons spanning a region of 135 kb on chromosome 22 band q11. Y5403 is a probe mix is based on a combination of DNA and PNA technology, and contains two FISH DNA probes and unlabeled PNA blocking probes. The FISH DNA probes are a mixture of a Texas Red-labeled DNA probe (BCR-Upstream) covering 333 kb centromeric to the BCR breakpoint cluster region and a fluorescein-labeled DNA probe (BCR-Downstream) covering 408 kb telomeric to the BCR breakpoint cluster region.

A protein encoded from breakpoint cluster region gene, has serine/threonine kinase activity. Fusion with abl protein causes leukemia... 

CML patients characteristically exhibit relative and absolute monocytosis in peripheral blood reminiscent of chronic myelomonocytic leukemia. Another distinct but rare fusion that has been described in t(9 22)-positive CML is one that results in the formation of a large 230kDa fusion protein as a consequence of a fusion between exon 19 (c3) of BCJ and exon 2 (a2) of ABL. The BCR breakpoints for this fusion are located in the micro breakpoint cluster region (jX-BCl ) located between exons 19 and 20 (see Figure 39-14). The p230 fusion is characteristic of a peculiar form of CML with prominent neutrophilic proliferation. The clinical course of p230-positive CML is reportedly indolent in the majority of cases. ... 

Borrow J, Goddard AD, Sheer D, Solomon E. Molecular analysis of acute promyelocytic leukemia breakpoint cluster region on chromosome 17. Science 1990 249 1577-80. 

Musacchio, A., Cantley, L. C., and Harrison, S. C. (1996). Crystal structure of the breakpoint cluster region-homology domain from phosphoinositide 3-kinase p85 alpha subunit. Proc. Natl. Acad. Sci. USA 93, 14373-14378. 

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