Analysis of ABL kinase domain mutations conferring resistance to tyrosine kinase inhibitors in chronic myeloid leukemia cases from India

Abstract

Background: The current study was undertaken to find out the frequency and distribution of ABL kinase domain (KD) mutations showing resistance to tyrosine kinase inhibitors (TKI) in CML patients from India.

Methods: A total of 24 TKI resistant CML patients were screened for ABL KD mutation by semi-nested reverse transcription PCR and sequencing. The expression of BCR-ABL transcripts was quantified by Real Time Taqman assay.

Results: Sixteen different point mutations were detected in 14 (58.3%) of 24 TKI resistant patients. Five out of the 16 mutations were located at the four hot spots of ABL kinase domain: one at the P-loop (Q252H), one at the imatinib binding site (T315I), two at the catalytic domain (M351, Y353F) and one at the active A loop (H396P). The three mutations, viz. M244V, T315I and A380V, were the most frequent mutations and accounted for 40.9% of all resistance associated mutations.

Conclusions: In the present study, the presence of ABL KD mutations was found to be a major cause of drug resistance. The T315I mutation was found to be resistant to second generation drugs such as dasatinib. The study reinforces the need for new therapeutic options which can target this mutation.