Breakpoint cluster region-Abelson tyrosine-protein kinase 1 E255V mutant (BCR-ABL1 E255V)

The Breakpoint cluster region-Abelson tyrosine-protein kinase 1 (BCR-ABL1) E255V mutant is a clinically significant variant of the oncogenic fusion protein responsible for chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) [1, 13]. This specific mutation involves a substitution of glutamic acid with valine at position 255 within the P-loop (ATP-binding loop) of the ABL1 kinase domain [2, 10]. The E255V mutation confers high-level resistance to first-generation tyrosine kinase inhibitors (TKIs) like imatinib and second-generation TKIs like nilotinib by altering the conformation of the ATP-binding pocket [4, 14]. Despite this mutation, the protein maintains constitutive tyrosine kinase activity, driving aberrant signal transduction through the RAS-MAPK, PI3K-AKT, and JAK-STAT pathways to promote cell survival and proliferation [16]. While third-generation TKIs such as ponatinib and allosteric inhibitors like asciminib show activity against this mutant, E255V remains a marker of poor prognosis and is often associated with disease progression to accelerated or blast phases [1, 17]. Management of patients harboring this mutation requires careful selection of TKIs and frequent monitoring for the emergence of additional compound mutations [3, 19]. Structural studies indicate that the valine substitution disrupts the hydrogen bonding network required for optimal inhibitor binding. Clinical detection of E255V is typically performed using Sanger sequencing or next-generation sequencing of the BCR-ABL1 kinase domain. Overall, the E255V mutant represents a major challenge in the precision treatment of Philadelphia chromosome-positive leukemias.

Other names

BCR-ABL1 E255VBCR-ABL E255Vp210 BCR-ABL E255VABL1 E255V

Tyrosine kinase inhibition via ATP-competitive binding (Type I and II inhibitors) or allosteric inhibition of the myristoyl pocket (STAMP inhibitors).