Promoter Hypermethylation of ATG16L2, TFAP2A, EBF2, Calcitonin, ABL1 Kinase Domain T315I Mutation Association with Imatinib Therapy Resistance and Median Survival in CML Patients of North-East India

Abstract

Background and Objectives: Chronic myeloid leukemia (CML) initiation and progression is regulated by epigenetic and genetic alterations. Imatinib therapy resistance in CML patients is important clinical issue. To understand association of kinase domain mutation and promoter hypermethylation of genes with imatinib therapy resistance hold significance in CML patients of North-East India. This study is a hospital based cross sectional study. Methods: A total of Sixty three (n=63) CML patients undergone imatinib mesylate were enrolled for the study. ABL kinase domain T315I mutation was analyzed by Allele specific- PCR (AS-PCR) and confirmed by sequencing. Promoter hypermethylation was analyzed by Methylation specific PCR (MS-PCR). The Chi square test and Fisher exact test used in SPSS ver19. Results: Tyrosine Kinase domain mutation T315I was found in 30.1% (19/63). The promoter hypermethylation of Calcitonin, ATG16L2, TFAP2A, EBF2 gene was detected in 42.9% (n=27), 28.6% (n=18), 38.1% (n=24), 27% (n= 17) CML patients respectively. Median relapse free survival was 21 months and statistically significant for CML patients without T315I mutation compared to patients with T315I mutation who has 12 months median relapse free survival (p=0.005). Median survival was 19 months for patients without EBF2 promoter hypermethylation and also statistically significant compared to CML patients with promoter hypermethylation (12 months) (p=0.026). Interpretation and Conclusions: We conclude that among imatinib resistant CML patients of North- East India harbouring T315I mutation of ABL1 Kinase domain and promoter hypermethylation of EBF2 gene have significantly lower median relapse free survival.

Keywords

• chronic myeloid leukemia, t315i mutation, promoter hypermethylation, imatinib mesylate, median survival, north-east india