Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein (BCR-ABL1) (BCR-ABL1)

The Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1) fusion protein is a constitutively active non-receptor tyrosine kinase resulting from the reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome (National Cancer Institute, 2024). This fusion protein plays a central role in the pathogenesis of Chronic Myeloid Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL) by activating multiple downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and JAK/STAT, which promote uncontrolled cell proliferation and survival (StatPearls, 2023). BCR-ABL1 is the primary therapeutic target for tyrosine kinase inhibitors (TKIs), which have transformed CML from a fatal disease into a manageable chronic condition (Apperley, 2015). First-generation TKIs like imatinib bind to the ATP-binding site, while subsequent generations (dasatinib, nilotinib, bosutinib, and ponatinib) were designed to overcome resistance caused by kinase domain mutations and often inhibit related kinases such as ABL2, SRC, KIT, and PDGFR (Huang et al., 2022). More recently, allosteric inhibitors such as asciminib have been developed to target the myristoyl pocket, providing a distinct mechanism to combat resistance, particularly the T315I gatekeeper mutation (UniProt, 2024).

Other names

Philadelphia chromosomeBCR-ABLp210 BCR-ABLp190 BCR-ABLp230 BCR-ABLBCR-ABL1 fusion proteinAbelson murine leukemia viral oncogene homolog 1ABL1ABL2c-AblARG

Tyrosine kinase inhibitors (TKIs) target BCR-ABL1 through two primary mechanisms: competitive inhibition of the ATP-binding site, which prevents the transfer of phosphate to substrate proteins, and allosteric inhibition, which binds to the myristoyl pocket to lock the kinase in an inactive conformation (Huang et al., 2022; UniProt, 2024). By blocking the kinase activity, these drugs interrupt downstream signaling cascades that drive leukemogenesis (StatPearls, 2023).