Variant Isoforms of BCR-ABL1 in Chronic Myelogenous Leukemia Reflect Alternative Splicing of ABL1 in Normal Tissue – Letter.
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Variant Isoforms of BCR-ABL1 in Chronic Myelogenous Leukemia Reflect Alternative Splicing of ABL1 in Normal Tissue – Letter.
Mol Cancer Ther. 2010 Jun 22;
Authors: Khorashad JS, Milojkovic D, Reid AG
Routine sequencing of the BCR-ABL kinase domain for the identification of resistance-associated point mutations is now a critical aspect of the management of chronic myeloid leukemia patients showing suboptimal response to imatinib. The recent correspondence between Lee and Santamaria (1-3) regarding the expression of an aberrant isoform of BCR-ABL1 in chronic myelogenous leukemia (CML) and the observation that the same insertion variant occurs in normal individuals (2) is therefore timely and relevant. In our experience and that of other groups, alternative splicing of BCR-ABL1 is not restricted to the BCR-ABL1(ins35) transcript reported by Lee et al. (1), but includes a variety of other isoforms (4, 5). The most common aberrant transcript we have observed harbored a deletion of exon 7 of ABL1 [ABL1(del7); identified in 82 of 236 (34%) CML patients]. Less common recurrent variations include complete or partial deletion of one or more ABL1 exons between 4 and 9, sometimes accompanied by partial insertion of intronic sequences. Although Lee and others have proposed a role for some of these splice variants in modulating BCR-ABL1 activity (1, 2), we found no correlation between the presence of a variant transcript and clinical features or likelihood of treatment response in patients with CML. Using the common exon 7 deletion as a model, we screened for the presence of similar alternative splicing of native ABL1 in normal individuals by reverse transcription-PCR and Scorpions-based allele-specific oligonucleotide PCR. Importantly, an ABL1(del7) transcript was detected in 4 of 17 normal cDNA samples. These observations argue against the notion that excision of exon 7 of ABL1 by alternative splicing is exclusively associated with CML and contradict the proposal of tyrosine kinase inhibitor therapy as a causative factor. Based on predictive analysis of protein structure, loss of exon 7 would confer no obvious novel function to the ABL1 molecule. Similarly, Sherbenou et al. (5) showed that BCR-ABL1 mutants lacking all or part of ABL1 exon 4 were catalytically inactive and did not interfere with the oncogenic activity of native BCR-ABL1. The expression of nonfunctional splice variants is not without precedent. Data generated by the ENCODE project indicate that many genes undergo a low level of alternative splicing, with little evidence to suggest that the alternative isoforms have a role as functional proteins (6). In the context of the clinical management of CML, it is therefore plausible that at least a proportion of the aberrantly spliced BCR-ABL1 transcripts are epiphenomena with no significant impact on disease course. The suggestions that expression of the BCR-ABL1(ins35) isoform increases relative to native BCR-ABL1 with prolonged exposure to imatinib and that the transcript is associated with resistance (1) are intriguing. However, such observations should be viewed with caution pending systematic validation using serial samples from imatinib-treated patients with a range of treatment responses and a sensitive means of quantifying relative expression of normal and aberrant transcripts. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.
PMID: 20571070 [PubMed - as supplied by publisher]