Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 fusion protein (p185 BCR-ABL) (p185 BCR-ABL)

The p185 BCR-ABL fusion protein is a constitutively active tyrosine kinase resulting from the Philadelphia chromosome translocation, t(9;22)(q34;q11) (National Cancer Institute, 2023). This specific isoform, also frequently designated as p190, is generated by the fusion of the BCR gene's first exon (e1) to the ABL1 gene's second exon (a2) (UniProt, P11274). It is the hallmark oncoprotein and primary driver of Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL), and is less commonly found in Chronic Myeloid Leukemia (CML) (PubMed, 30232150). The unregulated kinase activity of p185 BCR-ABL activates several downstream signaling cascades, including the RAS/MAPK, PI3K/AKT, and JAK/STAT pathways, which collectively promote malignant cell proliferation and survival (PubMed, 28103469). Therapeutically, this protein is the primary target for tyrosine kinase inhibitors (TKIs) such as Imatinib, Dasatinib, and Ponatinib, which bind to the ATP-binding site to block phosphorylation (StatPearls, NBK531481). Despite the success of TKIs, clinical management is often complicated by the development of point mutations in the ABL1 kinase domain, such as the T315I mutation, which render the protein resistant to many standard therapies (PubMed, 32735224).

Other names

p190 BCR-ABLBCR-ABL p185e1a2 BCR-ABL1Philadelphia chromosome fusion protein

Tyrosine kinase inhibition via competitive binding to the ATP-binding site or allosteric inhibition of the ABL kinase domain (StatPearls, NBK531481).