BCR-ABL1 tyrosine kinase (BCR-ABL1)

BCR-ABL1 is a constitutively active tyrosine kinase fusion protein formed by the reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome (National Cancer Institute, 2023). This oncoprotein is the defining molecular driver of Chronic Myeloid Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL), where it triggers aberrant signaling through the PI3K/AKT, JAK/STAT, and RAS/MAPK pathways to promote cell survival and proliferation (UniProt P00519). The specific cell populations mentioned, Ph+ leukemia cells and CML CD34+ cells, represent the malignant clones and the primitive stem cell compartment, respectively; the latter is particularly significant as it often exhibits resistance to standard therapies and can lead to disease relapse (Bhatia et al., Blood, 2003). Therapeutic management centers on Tyrosine Kinase Inhibitors (TKIs) like imatinib, which competitively inhibit the ATP-binding site, and newer agents like asciminib that target the myristoyl pocket (Nature Reviews Cancer, 2021). Despite high response rates, the emergence of point mutations such as T315I and the persistence of quiescent CD34+ leukemic stem cells remain the primary challenges in achieving treatment-free remission.

Other names

Philadelphia chromosome fusion proteinBCR-ABLP210 proteinP190 proteinPh+ leukemia cellsCML CD34+ progenitor cells

Inhibition of the BCR-ABL1 tyrosine kinase activity by binding to the ATP-binding site (Type I and II inhibitors) or the myristoyl allosteric pocket (Specifically Targeting the ABL Myristoyl Pocket or STAMP inhibitors), thereby blocking downstream oncogenic signaling pathways such as PI3K/AKT and RAS/MAPK (Nature Reviews Cancer, 2021).