Molecular Anatomy Of The Bcrabl Fusion

The breakpoints in ABL are spread over a large genomic region and may occur 5' of ABL exon Ib, between ABL exons Ia and II or, most frequently, between the two alternative first ABL exons (Figure 17.2) (reviewed in Ref. 36). Despite this variation, the ABL portion in the fusion mRNA and protein is usually constant, encompassing ABL exons 2-11. This is thought to be the result of posttranscriptional processing of the primary transcript. In contrast, the breakpoints in BCR localize to three distinct breakpoint cluster regions (bcr),16 which are associated with the three major types of Bcr-Abl fusion proteins. Breaks in the minor bcr (m-bcr) give rise to an e1a2 fusion mRNA and a 190-kd protein (p190BCR-ABL) that is found in two-third of patients with Ph-chromosome-positive acute lymphoblastic leukemia (ALL) and in rare patients with CML. Unlike typical CML, these patients are characterized by monocytosis.37 Breaks in the major bcr (M-bcr) result in e13a2 or e14a2 fusion mRNAs (previously referred to as b2a2 and b3a2, according to the original numbering of exons within the major breakpoint cluster region) and a 210-kd protein (p210BCR-ABL). p210BCR-ABL is typical of CML but also occurs in one-third of patients with Ph-chromosome-positive ALL.36 Many efforts were made toward identifying consistent differences between patients expressing e13a2 (b2a3) or b14a2 (b3a2). However, the only association that seems to stand the test of time is the notion of slightly higher platelet counts in patients with e14a2 tran-scripts.38 The third recognized cluster, termed micro-bcr (^-bcr), is localized in BCR intron 19 and generates a 230-kd protein (p230BCR-ABL) that is associated with the rare and relatively benign condition of chronic neutrophilic leukemia.39 The fact that the Abl portion

Bcr Abl Breakpoints

Figure 17.2 Location of the breakpoints in BCR and ABL and structure of the various BCR-ABL mRNAs. Breakpoints in ABL are spread over a large genomic region and may occur upstream of exon Ib, between exons la and II, or between exons Ib and la. In contrast, breakpoints in the BCR cluster in defined breakpoint cluster regions (bcr), a fact that led to the gene's naming. ABL exons 2-11 are contained in the BCR-ABL mRNA, regardless of the breakpoint location, as a result of splicing. In contrast, different types of fusion mRNA and protein are generated from the different breakpoint cluster regions in BCR. (Reproduced from Deininger et al.: Blood 96:3343, 2000; with permission)

Figure 17.2 Location of the breakpoints in BCR and ABL and structure of the various BCR-ABL mRNAs. Breakpoints in ABL are spread over a large genomic region and may occur upstream of exon Ib, between exons la and II, or between exons Ib and la. In contrast, breakpoints in the BCR cluster in defined breakpoint cluster regions (bcr), a fact that led to the gene's naming. ABL exons 2-11 are contained in the BCR-ABL mRNA, regardless of the breakpoint location, as a result of splicing. In contrast, different types of fusion mRNA and protein are generated from the different breakpoint cluster regions in BCR. (Reproduced from Deininger et al.: Blood 96:3343, 2000; with permission)

in the different fusion proteins is constant while the Bcr portion is variable provides circumstantial evidence that the transforming principle is likely to reside in Abl, while the Bcr part appears to modify the disease phenotype, with retention of a larger BCR portion rendering the disease less aggressive. Although the three major types of BCR-ABL fusion mRNA account for more than 99% of cases of Bcr-Abl-positive leukemia, many more BCR-ABL variants have been seen in anecdotal cases or small series of patients.38 Most of these variants have atypical breakpoints in BCR, generating fusion mRNAs, such as e6a240 or e8-insert-a2, where the open reading frame is retained by interposition of intronic sequences. However, fusions between BCR exon 1 and ABL exon 3 have also been described in CML patients.41 Due to the small numbers of reported cases, it has been difficult to convincingly ascribe a particular clinical phenotype to any of these rare BCR-ABL variants; however, the general theme seems to be that the retention of more BCR sequences within the fusion protein attenuates the disease, consistent with the observations in the major types of Bcr-Abl fusion proteins.

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