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

Jaroslav Jelinek, Vazganush Gharibyan, Marcos R.H. Estecio, Kimie Kondo, Rong He, Woonbok Chung, Yue Lu, Nianxiang Zhang, Shoudan Liang, Hagop M. Kantarjian, Jorge E. Cortes, Jean Pierre J. Issa

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere22110
JournalPloS one
Volume6
Issue number7
DOIs
StatePublished - Jul 13 2011
Externally publishedYes

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Disease Resistance
DNA methylation
DNA Methylation
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
leukemia
disease course
Disease Progression
Genes
Methylation
Survival
methylation
genes
suppressor genes
bisulfites
src Genes
interferon-alpha
Suppressor Genes
CpG Islands
K562 Cells
Imatinib Mesylate

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

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

In: PloS one, Vol. 6, No. 7, e22110, 13.07.2011.

Research output: Contribution to journalArticle

Jelinek, J, Gharibyan, V, Estecio, MRH, Kondo, K, He, R, Chung, W, Lu, Y, Zhang, N, Liang, S, Kantarjian, HM, Cortes, JE & Issa, JPJ 2011, 'Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia', PloS one, vol. 6, no. 7, e22110. https://doi.org/10.1371/journal.pone.0022110
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. / Aberrant DNA methylation is associated with disease progression, resistance to imatinib and shortened survival in chronic myelogenous leukemia. In: PloS one. 2011 ; Vol. 6, No. 7.
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