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

Tyrosine-protein kinase ABL1 is a non-receptor tyrosine kinase that plays a critical role in regulating cell growth, survival, and morphogenesis (UniProt: P00519). In its physiological state, ABL1 shuttles between the nucleus and cytoplasm, participating in DNA damage responses and actin cytoskeleton remodeling (PubMed: 11459964). However, the protein is most clinically significant when the ABL1 gene on chromosome 9 undergoes a reciprocal translocation with the BCR gene on chromosome 22, forming the Philadelphia chromosome and the resulting BCR-ABL fusion protein (StatPearls: NBK531481). This fusion protein exhibits constitutive tyrosine kinase activity, driving uncontrolled cell proliferation and inhibiting apoptosis, which is the primary driver of Chronic Myeloid Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL) (NIH: National Cancer Institute). Therapeutic intervention focuses on Tyrosine Kinase Inhibitors (TKIs) like imatinib, which bind to the ATP-binding site or allosteric sites to block signaling (PubChem: CID 5291). While TKIs have transformed CML into a manageable chronic condition, challenges remain, including the development of resistance through point mutations like T315I and off-target toxicities such as cardiotoxicity (PubMed: 28637664).

Other names

Abelson murine leukemia viral oncogene homolog 1c-ABLp150BCR-ABL1 fusion proteinProto-oncogene c-Ablv-abl Abelson murine leukemia viral oncogene homolog 1

Competitive inhibition of the ATP-binding site within the kinase domain or allosteric inhibition via the myristoyl binding pocket to prevent autophosphorylation and downstream signaling cascades.