Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) and Abelson-class fusion tyrosine kinase (BCR-ABL1 / ABL-class fusions)

BCR-ABL1 is a chimeric protein resulting from the reciprocal translocation between chromosomes 9 and 22, commonly referred to as the Philadelphia chromosome (t(9;22)) (StatPearls, 2023). This fusion creates a constitutively active non-receptor tyrosine kinase that bypasses normal regulatory mechanisms to drive malignant transformation in hematopoietic stem cells (UniProt P00519). ABL-class fusions represent a broader category of rearrangements involving genes such as ABL1, ABL2, PDGFRB, and CSF1R, which share a similar signaling signature and are characteristic of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) (NCI, 2024). These kinases activate multiple downstream signaling pathways, including JAK/STAT, PI3K/AKT/mTOR, and Ras/MAPK, leading to increased cell proliferation and the inhibition of apoptosis (PubMed, 2021). They are the primary therapeutic targets for tyrosine kinase inhibitors (TKIs), such as imatinib, dasatinib, and ponatinib, which bind to the ATP-binding site or allosteric sites to inhibit enzymatic activity (FDA, 2023). While TKIs have significantly improved survival rates, the emergence of resistance mutations, most notably the T315I gatekeeper mutation, remains a significant clinical challenge (PubMed, 2022). Monitoring of molecular response through quantitative PCR of transcript levels is essential for managing patients and detecting early signs of relapse (NIH, 2023).

Other names

BCR-ABL1 (StatPearls, 2023)ABL-class fusions (NCI, 2024)Philadelphia chromosome (StatPearls, 2023)Ph-like fusions (NCI, 2024)p210 BCR-ABL (PubMed, 2021)p190 BCR-ABL (PubMed, 2021)ABL-class rearrangements (NCI, 2024)

ATP-competitive inhibition of the tyrosine kinase domain or allosteric inhibition of the myristoyl pocket to prevent the kinase from adopting an active conformation (StatPearls, 2023; FDA, 2023).