title: HOXA4 gene promoter hypermethylation as an epigenetic mechanism mediating resistance to imatinib mesylate in chronic myeloid leukemia patients.
abstract: Development of resistance to imatinib mesylate (IM) in chronic myeloid leukemia (CML) patients has emerged as a significant clinical problem. The observation that increased epigenetic silencing of potential tumor suppressor genes correlates with disease progression in some CML patients treated with IM suggests a relationship between epigenetic silencing and resistance development. We hypothesize that promoter hypermethylation of HOXA4 could be an epigenetic mechanism mediating IM resistance in CML patients. Thus a study was undertaken to investigate the promoter hypermethylation status of HOXA4 in CML patients on IM treatment and to determine its role in mediating resistance to IM. Genomic DNA was extracted from peripheral blood samples of 95 CML patients (38 good responders and 57 resistant) and 12 normal controls. All samples were bisulfite treated and analysed by methylation-specific high-resolution melt analysis. Compared to the good responders, the HOXA4 hypermethylation level was significantly higher (P = 0.002) in IM-resistant CML patients. On comparing the risk, HOXA4 hypermethylation was associated with a higher risk for IM resistance (OR 4.658; 95% CI, 1.673-12.971; P = 0.003). Thus, it is reasonable to suggest that promoter hypermethylation of HOXA4 gene could be an epigenetic mechanism mediating IM resistance in CML patients.
authors.affiliation: Human Genome Centre, School of Medical Sciences, Universiti Sains Malaysia, Health Campus 16150 Kubang Kerian, Kelantan, Malaysia.
authors.forename: Marjanu Hikmah
authors.initials: MH
authors.lastname: Elias
authors.forename: Abdul Aziz
authors.initials: AA
authors.lastname: Baba
authors.forename: Azlan
authors.initials: A
authors.lastname: Husin
authors.forename: Sarina
authors.initials: S
authors.lastname: Sulong
authors.forename: Rosline
authors.initials: R
authors.lastname: Hassan
authors.forename: Goh Ai
authors.initials: GA
authors.lastname: Sim
authors.forename: S Fadilah
authors.initials: SF
authors.lastname: Abdul Wahid
authors.forename: Ravindran
authors.initials: R
authors.lastname: Ankathil
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D019175:DNA Methylation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D020868:Gene Silencing / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000096:biosynthesis*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D010879:Piperazines / Q000008:administration & dosage*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000008:administration & dosage*; D014157:Transcription Factors
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D018398:Homeodomain Proteins; D010879:Piperazines; D011743:Pyrimidines; D014157:Transcription Factors; C073547:HOXA4 protein, human; D000068877:Imatinib Mesylate