Molecular anatomy of Bcrabl translocations

In 1960, Nowell and Hungerford described a consistent chromosomal abnormality in CML patients, an acrocentric chromosome that was thought to represent a chromosomal deletion. This was the first example of a chromosomal abnormality linked to a specific malignancy. As chromosomal banding techniques improved, it became apparent that the abnormality was a shortened chromosome 22. Rowley later clarified that the shortened chromosome, the so-called Philadelphia chromosome, was the product of a reciprocal translocation between the long arms of chromosomes 9 and 22, t(9:22)(q34;q11) (Figure 7.1). The molecular consequence of this translocation is the fusion of the ABL gene from chromosome 9 to sequences on chromosome 22, the breakpoint cluster region (BCR), giving rise to a chimeric BCR-ABL gene.

The breakpoints within the ABL gene at 9q34 can occur anywhere over a large area (greater than 300 kb) at its 5' end—upstream of the first alternative exon Ia, downstream of the second alternative exon Ib, or, more frequently, between the two (Figure 7.2). Regardless of the exact location of the breakpoint, splicing of the primary hybrid transcript yields an mRNA molecule in which BCR sequences are fused to the second exon of ABLI, exon a2. In the majority of patients with CML and in approximately one-third of patients

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