Is the BCR-ABL1 transcript type in chronic myeloid leukaemia relevant?

Excerpt

In a recent edition of Medical Oncology, Bennour et al. [1] describe differences between the two most common BCR-ABL1 transcript types in a cohort of patients with chronic myeloid leukaemia (CML) in relation to the presenting age and platelet count. The BCR-ABL1 oncogene is the molecular hallmark of CML that results from the fusion of BCR on chromosome 22q11 to the ABL1 gene on chromosome 9q34. Several BCR-ABL1 transcript types may be generated, usually dependent upon which exon of BCR is fused to which exon of ABL1. The two most common forms of BCR-ABL1 are b2a2 (e13a2) and b3a2 (e14a2) that are expressed in >95 % of CML patients. A plethora of less common BCR-ABL1 variant transcripts have been reported that result from insertions, deletions (or both), breakpoints within exons or due to a fusion of alternative BCR and/or ABL1 exons [2]. These rare BCR-ABL1 variants have provided some insight into the molecular pathogenesis of CML. For example, the e1a2 BCR-ABL1 fusion generally results in a monocytic phenotype with patients having a poor response to tyrosine kinase inhibitors (TKI) and a high incidence of progression to accelerated and blast crisis phases of the disease, whereas those CML patients with the e19a2 BCR-ABL1 fusion generally have a more neutrophilic phenotype with good overall responses to TKI (Fig. 1). These genotype–phenotype differences are seemingly attributable to the presence or absence of the encoded functional domains of the BCR-ABL1 protein that contributes to altered cellular adhesion, enhanced proliferation, inhibition of apoptosis and increased genomic instability in CML. Identification of these rare BCR-ABL1 variants at presentation is also important for determining the correct primer/probe combinations necessary for quantitative PCR monitoring of residual disease that provides information on the kinetics of response to TKI and correlates with progression-free survival.

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