Tyrosine-protein kinase BCR-ABL1 (BCR-ABL1)

Tyrosine-protein kinase BCR-ABL1 is a constitutively active chimeric enzyme resulting from the reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome [1.3.1, 1.4.2]. This fusion protein combines the Breakpoint Cluster Region (BCR) with the Abelson murine leukemia viral oncogene homolog 1 (ABL1), leading to the loss of the ABL1 autoinhibitory domain and subsequent uncontrolled kinase activity [1.4.2]. BCR-ABL1 is the primary oncogenic driver in Chronic Myeloid Leukemia (CML) and a significant subset of Acute Lymphoblastic Leukemia (ALL), where it activates multiple downstream signaling pathways such as PI3K/AKT, JAK/STAT, and RAS/MAPK [1.3.1, 1.4.1]. These pathways promote rapid cell proliferation, enhance survival by inhibiting apoptosis, and alter cell adhesion properties in the bone marrow [1.3.1, 1.3.3]. The development of tyrosine kinase inhibitors (TKIs) has revolutionized treatment, with first-generation (imatinib), second-generation (dasatinib, nilotinib, bosutinib), and third-generation (ponatinib) drugs targeting the ATP-binding site [1.3.1, 1.3.4]. More recently, asciminib was introduced as an allosteric inhibitor that binds to the myristoyl pocket, providing a novel mechanism to overcome resistance [1.4.2]. Despite these advances, the emergence of point mutations in the kinase domain, particularly the T315I gatekeeper mutation, and various off-target toxicities like cardiotoxicity and pleural effusion remain critical challenges in clinical management [1.1.1, 1.1.4, 1.4.4].

Other names

BCR-ABLPhiladelphia chromosomep210 BCR-ABLp190 BCR-ABLp230 BCR-ABLBCR-ABL1 fusion proteinBCR-ABL1

Inhibition of the constitutively active tyrosine kinase activity through ATP-competitive binding or allosteric modulation of the myristoyl pocket [1.3.1, 1.4.2].