Breakpoint cluster region-Abelson tyrosine kinase (BCR-ABL) (BCR-ABL)

BCR-ABL is a constitutively active tyrosine kinase resulting from the reciprocal translocation between chromosomes 9 and 22, commonly referred to as the Philadelphia chromosome (t(9;22)(q34;q11)) [NCBI, PMC3524989]. This fusion protein is the hallmark of Chronic Myeloid Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL), where it drives oncogenesis by activating multiple signaling pathways, including PI3K/Akt, RAS/MAPK, and JAK/STAT [UniProt P00519, StatPearls]. These pathways promote uncontrolled cell proliferation and the inhibition of apoptosis, leading to the expansion of leukemic clones [PubMed 12423331]. In the K562 cell line, a widely used model for CML, BCR-ABL expression is the primary driver of the cellular antiproliferative response to targeted therapies [PubMed 15956513]. Therapeutic management involves tyrosine kinase inhibitors (TKIs) like imatinib, which competitively bind the ATP-binding site, or newer allosteric inhibitors like asciminib [FDA, PubMed 34933345]. Despite the success of TKIs, clinical challenges include the emergence of resistance mutations, such as the T315I gatekeeper mutation, and potential off-target toxicities like cardiotoxicity or vascular events [PubMed 28106004].

Other names

BCR-ABL1Philadelphia chromosomep210 BCR-ABLp190 BCR-ABLp230 BCR-ABL

Tyrosine kinase inhibition via ATP-competitive binding or allosteric modulation.