Chronic Myeloid Leukemia Coverage from Every Angle

Identifying Imatinib-Resistant Mutations in Patients With CML

By: Joseph Fanelli
Posted: Tuesday, April 2, 2019

According to findings published in Scientific Reports, several novel mutations in the KD region of the BCR-ABL gene that cause nonfunctional protein formation were identified as potential culprits in resistance to imatinib in patients with chronic myeloid leukemia (CML). The findings highlight the need for genetic analysis to detect such mutations to guide therapeutic choices appropriately, concluded Chodimella Chandrasekhar, PhD, of the Sri Venkateswara Institute of Medical Science, India, and colleagues.

“The results highlight the need for the BCR-ABL gene sequence analysis in CML patients to understand any variations in the gene for designing therapeutic modalities such as dose elevation or considering second, third, and fourth generation drugs, as early as required, for good outcomes and long-term prognosis,” the researchers said.

In the study, 62 patients with Philadelphia chromosome–positive CML showing expression of the BCR-ABL gene were treated with imatinib. After confirmation of the diagnosis, 35 patients were in chronic phase, 21 patients were in accelerated phase, and 6 patients were in blast crisis. After 3 months, 21 patients did not obtain complete hematologic response and showed significant decrease in BCR-ABL gene expression. In all imatinib-resistant patients, the BCR-ABL gene was polymerase chain reaction amplified and sequenced.

The sequence analysis showed four novel missense mutations, six already reported mutations —which contributed to the formation of inactive enzyme—and two novel frameshift mutations that resulted in truncated protein formation. The four novel missense mutations were p.(Leu301Ile), p.(Tyr320His), p.(Glu373Asp), and p.(Asp381Asn). The six already reported mutations included p.(Val256Gly), p.(Thr315Ile), p.(Gly250Glu), p.(Tyr253His), p.(Phe317Leu), and p.(Met351Thr). The two newer frameshift mutations were p.(Glu281*) and p.(Tyr393*). The analysis also revealed that each of the mutations affected the P-loop, gatekeeper catalytic, and activation loop domain regions of the enzyme.

Disclosure: The study authors reported no conflicts of interest.

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