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

The Breakpoint cluster region-Abelson tyrosine-protein kinase (BCR-ABL) is an oncogenic fusion protein created by the reciprocal translocation between chromosomes 9 and 22, commonly referred to as the Philadelphia chromosome [1]. This genetic rearrangement results in a constitutively active tyrosine kinase that drives the pathogenesis of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) [2]. The BCR-ABL protein activates multiple downstream signaling pathways, including Ras/MAPK, PI3K/AKT, and JAK/STAT, which promote autonomous cell growth and provide resistance to programmed cell death [3]. Therapeutic management of these malignancies has been transformed by the development of small-molecule Tyrosine Kinase Inhibitors (TKIs) like imatinib, which competitively bind to the ATP-binding site of the kinase domain [4]. While highly effective, clinical challenges such as the emergence of resistance mutations, most notably the T315I gatekeeper mutation, have necessitated the development of second- and third-generation TKIs, as well as allosteric inhibitors like asciminib [5]. Many of these therapeutic agents also inhibit other tyrosine kinases, such as SRC, KIT, and PDGFR, which contributes to both their broad efficacy and their distinct side-effect profiles [6].

Other names

BCR-ABL1Philadelphia chromosome fusion proteinp210 BCR-ABLp190 BCR-ABLp230 BCR-ABL

Competitive inhibition of the ATP-binding site of the ABL kinase domain, or allosteric inhibition of the myristoyl pocket, preventing downstream phosphorylation and oncogenic signaling.