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Interplay of RUNX1/MTG8 and DNA methyltransferase 1 in acute myeloid leukemia.

The translocation t(8;21)(q22;q22) in acute myeloid leukemia (AML) results in the expression of the fusion protein RUNX1/MTG8, which in turn recruits histone deacetylases (HDAC) to silence RUNX1 target genes [e.g., interleukin-3 (IL-3)]. We previously reported that expression of the RUNX1/MTG8 target gene IL-3 is synergistically restored by the combination of inhibitors of HDACs (i.e., depsipeptide) and DNA methyltransferases (DNMT; i.e., decitabine) in RUNX1/MTG8-positive Kasumi-1 cells. Thus, we hypothesized that DNMT1 is also part of the transcriptional repressor complex recruited by RUNX1/MTG8. By a chromatin immunoprecipitation assay, we identified a RUNX1/MTG8-DNMT1 complex on the IL-3 promoter in Kasumi-1 cells and in primary RUNX1/MTG8-positive AML blasts. The physical association of RUNX1/MTG8 with DNMT1 was shown by coimmunoprecipitation experiments. Furthermore, RUNX1/MTG8 and DNMT1 were concurrently released from the IL-3 promoter by exposure to depsipeptide or stabilized on the promoter by decitabine treatment. Finally, we proved that RUNX1/MTG8 and DNMT1 were functionally interrelated by showing an enhanced repression of IL-3 after coexpression in 293T cells. These results suggest a novel mechanism for gene silencing mediated by RUNX1/MTG8 and support the combination of HDAC and DNMT inhibitors as a novel therapeutic approach for t(8;21) AML.

Pubmed ID: 15735013

Authors

  • Liu S
  • Shen T
  • Huynh L
  • Klisovic MI
  • Rush LJ
  • Ford JL
  • Yu J
  • Becknell B
  • Li Y
  • Liu C
  • Vukosavljevic T
  • Whitman SP
  • Chang KS
  • Byrd JC
  • Perrotti D
  • Plass C
  • Marcucci G

Journal

Cancer research

Publication Data

February 15, 2005

Associated Grants

  • Agency: NCI NIH HHS, Id: K08-CA90469
  • Agency: NCI NIH HHS, Id: P30-CA16058
  • Agency: NCI NIH HHS, Id: R01-CA102031
  • Agency: NCI NIH HHS, Id: R21-CA094552

Mesh Terms

  • Acute Disease
  • Cell Line
  • Cell Line, Tumor
  • Core Binding Factor Alpha 2 Subunit
  • DNA (Cytosine-5-)-Methyltransferase
  • DNA Methylation
  • DNA-Binding Proteins
  • Gene Expression Regulation, Neoplastic
  • Gene Silencing
  • Humans
  • Interleukin-3
  • Leukemia, Myeloid
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Transcription, Genetic
  • Transfection