Breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1) (BCR-ABL1)

Breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1) is a constitutively active chimeric tyrosine kinase produced by the reciprocal translocation between chromosomes 9 and 22, commonly referred to as the Philadelphia chromosome (NCI, 2023). This fusion protein is the primary oncogenic driver in chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia (ALL), where it activates signaling pathways such as RAS/MAPK, PI3K/AKT, and JAK/STAT to promote autonomous cell growth and survival (StatPearls, 2023). The development of imatinib, the first-in-class tyrosine kinase inhibitor (TKI), transformed CML from a fatal disease into a manageable chronic condition by specifically targeting the ATP-binding site of the ABL1 kinase domain (PubMed, 2021). Despite the success of TKIs, clinical challenges remain, particularly the emergence of resistance-conferring mutations like T315I, which necessitate the use of next-generation inhibitors or allosteric modulators like asciminib (UniProt, 2024). Monitoring the molecular response through quantitative PCR of BCR-ABL1 transcripts is the gold standard for managing patients on therapy and identifying early treatment failure (NIH, 2023).

Other names

BCR-ABLPhiladelphia chromosome fusion proteinp210 BCR-ABLp190 BCR-ABLp230 BCR-ABL

BCR-ABL1 is targeted by small-molecule inhibitors that typically bind to the ATP-binding site of the ABL1 kinase domain, preventing the phosphorylation of downstream substrates (StatPearls, 2023). Newer agents like asciminib utilize an allosteric mechanism by binding to the ABL myristoyl pocket, which induces an inactive conformation of the kinase (PubMed, 2021).