Breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 mutants (BCR-ABL1 mutants)

BCR-ABL1 is a chimeric fusion protein resulting from a reciprocal translocation between chromosomes 9 and 22, known as the Philadelphia chromosome (NCI, 2023). This fusion creates a constitutively active non-receptor tyrosine kinase that drives the pathogenesis of Chronic Myeloid Leukemia (CML) and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia (Ph+ ALL) by activating downstream signaling pathways like JAK/STAT, PI3K/AKT, and RAS/MAPK (Soverini et al., 2018, Blood). While first- and second-generation tyrosine kinase inhibitors (TKIs) like imatinib and dasatinib are effective, point mutations within the BCR-ABL1 kinase domain frequently emerge, leading to clinical resistance. The most notorious of these is the T315I 'gatekeeper' mutation, which creates steric hindrance that prevents most TKIs from binding to the ATP-binding pocket (Baccarani et al., 2019, Annals of Oncology). To overcome this resistance, third-generation inhibitors like ponatinib and allosteric inhibitors like asciminib have been developed to target these specific mutant forms (FDA, 2021; Rea et al., 2021, Lancet Oncology). Monitoring these mutations through molecular diagnostics is essential for guiding therapeutic transitions in leukemic patients.

Other names

Philadelphia chromosome fusion protein mutantsBCR-ABL tyrosine kinase mutantsp210 BCR-ABL mutantsp190 BCR-ABL mutantsBCR-ABL1 kinase domain mutants

Inhibition of the constitutively active tyrosine kinase activity by competing with ATP at the catalytic binding site (orthosteric inhibitors) or by binding to the myristoyl pocket to restore auto-inhibition (allosteric inhibitors) (Apperley, 2015, Hematology; Hughes & White, 2021, Blood).