BCR-ABL fusion tyrosine kinase (BCR-ABL)

The BCR-ABL fusion tyrosine kinase is an oncogenic protein resulting from the t(9;22) Philadelphia chromosome translocation, fusing the BCR gene on chromosome 22 with the ABL1 tyrosine kinase gene on chromosome 9. This fusion creates a constitutively active kinase with enhanced tyrosine kinase activity compared to native ABL1, due to loss of the ABL1 cap domain and BCR oligomerization domains that promote dimerization and autophosphorylation, stabilizing the open catalytic conformation. It drives leukemogenesis primarily in chronic myeloid leukemia (CML), but also in subsets of acute lymphoblastic leukemia (ALL), mixed phenotype acute leukemia (MPAL), and rarely acute myeloid leukemia (AML). The kinase phosphorylates downstream signaling proteins, dysregulating pathways that promote uncontrolled cell proliferation and survival. BCR-ABL exists in isoforms like p210 (common in CML), p185 (in Ph+ ALL), and p230, differing in BCR breakpoints and additional domains such as coiled-coil oligomerization and pleckstrin homology. It is a validated therapeutic target, with tyrosine kinase inhibitors (TKIs) like imatinib binding the inactive kinase conformation to block ATP access and inhibit activity. Resistance arises from mutations like T315I in the kinase domain, prompting second- and third-generation TKIs such as ponatinib. Degradation pathways involving E3 ligases like c-CBL also regulate its levels via ubiquitination.

Other names

BCR-ABL1 fusion proteinp210BCR-ABLp185BCR-ABLp230BCR-ABLPhiladelphia chromosome kinase

Tyrosine kinase inhibition, Binding to inactive kinase conformation, ATP-competitive inhibition, Stabilization of inactive DFG-out conformation