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[i-BCR (e19a2 junction)

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230-kd protein (p230BCR-ABL)

In rare cases of CML, but in about 50 percent of adult Ph-positive ALL and in 80 percent of childhood Ph-positive ALL, the breakpoint on chromosome 22 is located 5' of M-bcr within a long intron segment between alternative exon e2' and e2 called the minor breakpoint cluster region (m-bcr) (Figure 4-2).24 Splicing out exons el' and e2' results in an e1a2 junction BCR-ABL transcript that is translated into a smaller BCR-ABL fusion protein of 190 kd (pi90BcR-ABL).25,26 Both p210BCR-ABL and pi90BCR-ABL display increased and constitutive tyrosine phosphokinase activity compared to the normal ABL protein p145ABL. A third breakpoint location (|-bcr) within BCR has been identified that is located 3' from M-bcr between exons e19 and e20 generating a fusion transcript with an e19a2 junction. The translation product is a protein of 230 kd (p230BCR-ABL) (Figure 4-2).27,28 Consistent but low-level coexpression of p190BCR-ABL with p210BCR-ABL has been demonstrated in most patients with CML in chronic phase.29 If present in comparable levels to p210BCR-ABL, pi90BCR-ABL disease may be characterized by a prominent monocytic component,30'31 whereas the subgroup of patients who expressed p230BCR-ABL has been associated with the neutrophilic leukemia variant, a lower white blood cell count than usually observed, and a slower progression to blast crisis (Table 4-1).27

About two-thirds of patients with CML express the reciprocal ABL-BCR fusion gene on the derivative chromosome 9q+. The 5' part of ABL exon lb is fused to the 3' tail of BCR exons b3 or b4. No pathogenetic role has been ascribed to ABL-BCR. Earlier reports of a correlation of ABL-BCR expression with a better response to treatment with interferon-alpha have not been confirmed.32

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