title: Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia.
abstract: 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.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. jjelinek@mdanderson.org
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.forename: Vazganush
authors.initials: V
authors.lastname: Gharibyan
authors.forename: Marcos R H
authors.initials: MR
authors.lastname: Estecio
authors.forename: Kimie
authors.initials: K
authors.lastname: Kondo
authors.forename: Rong
authors.initials: R
authors.lastname: He
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.forename: Yue
authors.initials: Y
authors.lastname: Lu
authors.forename: Nianxiang
authors.initials: N
authors.lastname: Zhang
authors.forename: Shoudan
authors.initials: S
authors.lastname: Liang
authors.forename: Hagop M
authors.initials: HM
authors.lastname: Kantarjian
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Cortes
authors.forename: Jean-Pierre J
authors.initials: JP
authors.lastname: Issa
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001549:Benzamides; D045744:Cell Line, Tumor; D019175:DNA Methylation / Q000187:drug effects* / Q000235:genetics*; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D052138:Genes, Neoplasm / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010879:Piperazines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D017422:Sequence Analysis, DNA; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate