Synergistic antileukemic action of a combination of inhibitors of DNA methylation and histone methylation

Richard L. Momparler, Youssef Idaghdour, Victor E. Marquez, Louise F. Momparler

Research output: Contribution to journalArticlepeer-review

Abstract

DNA methylation and histone methylation are both involved in epigenetic regulation of gene expression and their dysregulation can play an important role in leukemogenesis. Aberrant DNA methylation has been reported to silence the expression of tumor suppressor genes in leukemia. Overexpression of the histone methyltransferase, EZH2, a subunit of the polycomb group repressive complex 2 (PRC2), was observed to promote oncogenesis. This is due to aberrant gene silencing by the trimethylation of histone H3 lysine 27 (H3K27me3) by EZH2. Since both these epigenetic silencing events are reversible, they are interesting targets for chemotherapeutic intervention by using an inhibitor of DNA methylation, such as 5-aza-2'-deoxcytidine (5-AZA-CdR), and 3-deazaneplanocin-A (DZNep), an inhibitor of the EZH2. Human HL-60 and murine L1210 leukemic cells exposed in vitro to 5-AZA-CdR and DZNep in combination showed a synergistic loss of clonogenicity in a colony assay as compared to each agent alone. This positive chemotherapeutic interaction was also observed in mice with L1210 leukemia. Quantitative PCR showed that the combination also produced a remarkable synergistic activation of the tumor suppressor genes, CDKN1A and FBXO32. Microarray analysis showed that 5-AZA-CdR plus DZNep produced a synergistic activation of >150 genes. Our results indicate that 5-AZA-CdR plus DZNep can reactivate target genes that are silenced by two distinct epigenetic mechanisms leading to a loss of the proliferative potential of leukemic cells.

Original languageEnglish (US)
Pages (from-to)1049-1054
Number of pages6
JournalLeukemia Research
Volume36
Issue number8
DOIs
StatePublished - Aug 2012

Keywords

  • 3-Deazaplanocin-A
  • 5-Aza-2'-deoxycytidine
  • Chemotherapy
  • DNA methylation
  • Gene expression
  • Histone methylation
  • Mouse model

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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