Breakpoint cluster region protein - Abelson tyrosine kinase fusion (BCR-ABL1)

BCR-ABL1 is a chimeric oncoprotein resulting from the reciprocal translocation between chromosomes 9 and 22, commonly referred to as the Philadelphia chromosome [5, 12]. This genetic event fuses the Breakpoint Cluster Region (BCR) gene with the Abelson murine leukemia viral oncogene homolog 1 (ABL1) gene, creating a constitutively active non-receptor tyrosine kinase [1, 14]. The unregulated activity of this kinase triggers multiple downstream signaling cascades, including the RAS/MAPK, PI3K/AKT, and JAK/STAT pathways, which promote uncontrolled cell proliferation and inhibit apoptosis [4, 5, 9]. BCR-ABL1 is the hallmark driver of Chronic Myeloid Leukemia (CML) and is also found in a subset of patients with Acute Lymphoblastic Leukemia (ALL) [1, 20]. Targeted therapies known as Tyrosine Kinase Inhibitors (TKIs), such as imatinib, dasatinib, and nilotinib, have transformed these leukemias into manageable chronic conditions by binding to the ATP-binding site or allosteric pockets of the protein [1, 15, 21]. Despite their success, therapeutic challenges persist, most notably the emergence of resistance mutations like T315I and safety concerns such as vascular occlusive events and pleural effusions [3, 6, 7]. Monitoring of BCR-ABL1 transcript levels is essential for assessing treatment efficacy and detecting early signs of relapse [5, 10]. The development of third-generation inhibitors like ponatinib and allosteric inhibitors like asciminib has expanded the treatment landscape for patients with resistant disease [6, 21].

Other names

Philadelphia chromosomePh chromosomep210 BCR-ABLp190 BCR-ABLp230 BCR-ABLc-ABLABLBCR-ABL

Tyrosine kinase inhibition (ATP-competitive or allosteric)