The Bcrabl Rearrangement

The Ph reciprocal translocation between the long arms of chromosomes 9 and 22 transposes the large 3' segment of ABL from chromosome 9q34 to the 5' part of BCR on chromosome 22q11 in a head-to-tail fashion, thus generating a hybrid BCR-ABL gene that is then transcribed into a chimeric BCR-ABL mRNA (Figure 4-2).20

The ABL (Abelson leukemia virus) gene is the protoonco-gene homologue of the viral transforming V-ABL gene that causes nonthymic pre-B-cell lymphomas in mice infected with the Abelson murine leukemia virus (A-MuLV).21 ABL is highly conserved in evolution and is found in virtually every vertebrate genome. It is located on 9q34, spans 230 kilobases (kb), and contains 11 exons that are oriented with their 5'-terminus toward the centromere. The gene has two distinct 5' exons, alternative exons 1b and 1a, of which exon 1b is separated by an intron of around 200 kb in the 5' direction of exons 1a and 2 to 11 (also referred to as a2 to a11) (Figure 4-2). Splicing either 5' sequence to the common set of the ten 3' exons creates two major ABL mRNAs of 6 kb and 7 kb, respectively (Table 4-1).22 Breaks in the ABL gene occur at variable sites in the long intron between exons 1b and 1a (i.e., usually 5' of ABL exon 2). Deletions of exon 2 and in-frame joining at the mRNA level of BCR sequences to ABL exon 3 have been described in CML but are rare.

In contrast, the breakpoint locations on chromosome 22q11 are rather restricted to a narrow sequence that occupies the central portion of the BCR (breakpoint cluster region) gene (previously also referred to as PHL). The BCR gene spans at least 90 kb and is normally transcribed into two mRNA molecules of 4.5 kb and 6.7 kb, respectively (Table 4-1). During the BCR-ABL translocation, ABL exons 2 to 11 are transposed into the major breakpoint cluster region (M-bcr) of BCR between exons 12 to 16 (also referred to as b1 to b5) which extends over 5.8 kb. The breakpoints are located either 5' on BCR between

Figure 4-2. Translocation t(9;22)(q34;q11) transposes ABL exons a2 to all from chromosome 9q34 into one of several breakpoint cluster regions (BCR) on chromosome 22q11. In most cases of patients with CML, the ABL exons are transposed into the major (M-) BCR resulting in a b2a2 or b3a3 fusion gene, a chimeric mRNA, and a fusion protein of 210 kd, called p210BCR-ABL. More frequently in Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) are the ABL exons fused to BCR exon e2 creating an e2a2 fusion gene that eventually is translated into a shorter protein of 190 kd, termed p190BCR-ABL. A third locus of transposition is |-BCR, which generates an e19a2 fusion and the largest fusion protein, p230BCR-ABL.

Figure 4-2. Translocation t(9;22)(q34;q11) transposes ABL exons a2 to all from chromosome 9q34 into one of several breakpoint cluster regions (BCR) on chromosome 22q11. In most cases of patients with CML, the ABL exons are transposed into the major (M-) BCR resulting in a b2a2 or b3a3 fusion gene, a chimeric mRNA, and a fusion protein of 210 kd, called p210BCR-ABL. More frequently in Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) are the ABL exons fused to BCR exon e2 creating an e2a2 fusion gene that eventually is translated into a shorter protein of 190 kd, termed p190BCR-ABL. A third locus of transposition is |-BCR, which generates an e19a2 fusion and the largest fusion protein, p230BCR-ABL.

exons b2 and b3 or 3' between exons b3 and b4. A BCR-ABL fusion gene is thus created with either a b2a2 or b3a2 junction.23 The chimeric 8.5 kb mRNA is translated into a fusion protein of 210 kd (p210BCR-ABL). In most cases, CML cells demonstrate either b2a2 or b3a2 transcripts, but in a small per centage both fusion proteins are expressed by alternative splicing events. Comparing the 5' with the 3' M-bcr breakpoint locations, no differences in response to treatment, prognosis, or clinical features exist except for a higher platelet count in patients with the b3a2 transcripts.23

Table 4-1

Characteristics of ABL, BCR, and BCR-ABL

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