Schematic representation of the ABL1 and BCR genes and the BCR-ABL1 kinase. (A) BCR contains 23 exons. Exons 1′ and 2′ of BCR are alternative exons within the first intron. The 3 main breakpoint cluster regions (m-bcr, M-bcr, and μ-bcr) in BCR are presented. ABL1 contains 2 alternative first exons (1b and 1a). The dashed arrows represent the breakpoints within ABL1. The combination of breakpoints within BCR and ABL1 genes generates different fusion transcripts encoding proteins with distinct molecular weights. (B) The structural modularity of SRC, ABL1b, and BCR-ABL1 kinases is shown. SRC and ABL1 kinases share a common central core (42% overall homology) composed of a tyrosine kinase domain, an SRC-homology-2 (SH2) domain, and an SH3 domain. The domains upstream of the SH3 domain and downstream of the kinase domain differ significantly between SRC and ABL1 kinases. The NH₂ terminus in ABL1 and BCR-ABL1 kinases is the “Cap” region. Two isoforms of ABL1 (human types 1a and 1b) are generated by alternative splicing of the first ABL1 exon. ABL1b contains a myristate site (Myr-NH) at the extreme end of the amino-terminal segment, which binds to the kinase domain and keeps the SH2-SH3 autoinhibitory structure in place (ie, in the “off state”). The homology region in SRC family kinase is the N-terminal membrane-localization domain (also referred to as the SH4 domain). Tyrosine phosphorylation sites are shown.