Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 and Abelson tyrosine kinase 1 and 2 (BCR-ABL1 and ABL1/2)

BCR-ABL1 is a chimeric fusion protein resulting from the reciprocal translocation t(9;22)(q34;q11), commonly referred to as the Philadelphia chromosome (National Cancer Institute, 2023). This genetic abnormality results in a constitutively active non-receptor tyrosine kinase that promotes oncogenic signaling pathways, such as Ras/MAPK and PI3K/Akt, leading to the pathogenesis of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) (StatPearls, 2023). ABL1 and ABL2 (also known as ARG) are the native cellular counterparts that regulate essential processes such as cytoskeletal remodeling, cell cycle progression, and DNA repair (UniProt P00519; UniProt P42684). Pharmacological targeting of these kinases is primarily achieved through tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib, which compete with ATP for binding to the kinase domain (PubMed, PMID: 28841406). More recently, allosteric inhibitors like asciminib have been developed to target the myristoyl pocket, providing a mechanism to overcome resistance caused by ATP-binding site mutations (FDA, 2021). Despite the success of these therapies, clinical management is often complicated by the emergence of resistance mutations, most notably the T315I gatekeeper mutation, and potential off-target toxicities such as myelosuppression and cardiovascular events (Journal of Hematology & Oncology, 2021).

Other names

BCR-ABL fusion proteinc-Ablc-ArgAbelson murine leukemia viral oncogene homolog 1Abelson-related geneABL1ABL2ARGPhiladelphia chromosome protein

Tyrosine kinase inhibition via ATP-competitive binding or allosteric modulation of the myristoyl pocket (PubMed, PMID: 28841406).