Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia

• Published in: PloS one 2011-07, Vol.6 (7), p.e22110
• Main Authors: Jelinek, Jaroslav, Gharibyan, Vazganush, Estecio, Marcos R H, Kondo, Kimie, He, Rong, Chung, Woonbok, Lu, Yue, Zhang, Nianxiang, Liang, Shoudan, Kantarjian, Hagop M, Cortes, Jorge E, Issa, Jean-Pierre J
• Format: Article
• Language: English
• Subjects: Aberration; Abl protein; Adolescent; Adult; Aged; Analysis; BCR protein; BCR-ABL protein; Benzamides; Bioinformatics; Biological response modifiers; Biology; Biopsy; Bisulfite; Cancer genetics; Care and treatment; CDKN2B gene; Cell Line, Tumor; Cervical cancer; Chronic myeloid leukemia; Colorectal cancer; CpG islands; Deoxyribonucleic acid; Development and progression; Disease Progression; Disease resistance; DNA; DNA methylation; DNA Methylation - drug effects; DNA Methylation - genetics; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epigenetic inheritance; Female; Fusion protein; Gene Expression Regulation, Leukemic - drug effects; Genes; Genes, Neoplasm - genetics; Genome, Human - genetics; Genomes; Humans; Imatinib; Imatinib Mesylate; Interferon; Kinases; Leukemia; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy; Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics; Male; Medicine; Methylation; Middle Aged; Multivariate Analysis; Mutation; Myeloid leukemia; Neoplasm Staging; Neoplasms; Oligonucleotide Array Sequence Analysis; Patients; Piperazines - adverse effects; Piperazines - pharmacology; Piperazines - therapeutic use; Pyrimidines - adverse effects; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Sequence Analysis, DNA; Studies; Sulfites; Survival; Survival Analysis; Translocation; Treatment Outcome; Tumors; Young Adult; α-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0022110

The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not completely understood. To elucidate its role we analyzed 120 patients with CML for methylation of promoter-associated CpG islands of 10 genes. Five genes were identified by DNA methylation screening in the K562 cell line and 3 genes in patients with myeloproliferative neoplasms. The CDKN2B gene was selected for its frequent methylation in myeloid malignancies and ABL1 as the target of BCR-ABL translocation. Thirty patients were imatinib-naïve (mostly treated by interferon-alpha before the imatinib era), 30 were imatinib-responsive, 50 were imatinib-resistant, and 10 were imatinib-intolerant. We quantified DNA methylation by bisulfite pyrosequencing. The average number of methylated genes was 4.5 per patient in the chronic phase, increasing significantly to 6.2 in the accelerated and 6.4 in the blastic phase. Higher numbers of methylated genes were also observed in patients resistant or intolerant to imatinib. These patients also showed almost exclusive methylation of a putative transporter OSCP1. Abnormal methylation of a Src suppressor gene PDLIM4 was associated with shortened survival independently of CML stage and imatinib responsiveness. We conclude that aberrant DNA methylation is associated with CML progression and that DNA methylation could be a marker associated with imatinib resistance. Finally, DNA methylation of PDLIM4 may help identify a subset of CML patients that would benefit from treatment with Src/Abl inhibitors.