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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.

Aberrant DNA Methylation Is Associated with Disease Progression, Resistance to Imatinib and Shortened Survival in Chronic Myelogenous Leukemia