Importance of BCR/ABL1 Transcript Type in CML

Abstract

<h3>Introduction</h3> The <i>BCR/ABL1</i> fusion exists in several different isoforms, depending on the precise position of the t(9;22)(q34;q11) genomic breakpoints in each case. In chronic myeloid leukemia (CML), the two most common isoforms are known as e13a2 and e14a2, which are shorthand for mRNA fusions of <i>BCR</i> exon 13 or <i>BCR</i> exon 14, respectively, to <i>ABL1</i> exon 2. Historically, these two fusions were referred to as b2a2 and b3a2, with b2 (<i>BCR</i> exon 13) and b3 (<i>BCR</i> exon 14) corresponding to the second and third exons within the classically-defined 5.8-kb major breakpoint cluster region (M-BCR) within <i>BCR.</i>¹ Both e13a2 and e14a2 encode a 210-kDa BCR/ABL1 protein (p210), but e14a2 encodes a chimeric protein that is 25 amino acids larger than e13a2, corresponding to the 75 bp of <i>BCR</i> exon 14. At the genomic DNA level, the chromosome 22 breakpoint typically occurs in <i>BCR</i> intron 13 for e13a2 and <i>BCR</i> intron 14 for e14a2. Collectively, e13a2 and e14a2 <i>BCR/ABL1</i> account for 98% of CML cases, with the majority of these expressing e14a2. Approximately 10% of cases express both isoforms.^1,2 A large international survey of CML cases found small but significant differences in the relative prevalence of the two fusions in relation to age and gender, with e13a2 being more frequent in males and less common in the elderly.²