Exon-skipping in BCR/ABL is induced by ABL exon 2

The BCR/ABL fusion gene is pathognomonic for chronic myelogenous leukaemia (CML), We have previously reported alternative splicing of BCR/ABL, as indi cated by the detection of both p190- and p210-encoding transcripts, in abou t 60% of CML patient samples. These exon-skipping events involved the joini ng of ABL exon 2 to variable upstream BCR exons, Similarly, ABL exon 2 is a lternatively spliced to either of two upstream ABL exons (1a or 1b) in c-AB L, We have constructed BCR and BCR/ABL minigenes to study this phenomenon i n more detail. These constructs were transfected into various cell types an d splicing was assessed by reverse transcriptase PCR, Whereas the basic BCR minigene expressed exon-inclusive transcripts only, insertion of genomic D NA spanning ABL exon 2 induced exon-skipping but only when expressed in the CML cell lines K562 and EM3, In this study we localized the required seque nce element to ABL exon 2 itself. These results mimic the splicing phenotyp e displayed by most CML patients. We propose a model where a trans-factor p resent in some CML cells interacts with ABL exon 2 pre-mRNA to promote skip ping of upstream BCR exons.