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

Shujun Liu, Tiansheng Shen, Lenguyen Huynh, Marko I. Klisovic, Laura J. Rush, Jamie L. Ford, Jianhua Yu, Brian Becknell, Yu Li, Chunhui Liu, Tamara Vukosavljevic, Susan P. Whitman, Kun Sang Chang, John C. Byrd, Danilo Perrotti, Christoph Plass, Guido Marcucci

Research output: Contribution to journalArticlepeer-review

120 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1277-1284
Number of pages8
JournalCancer Research
Volume65
Issue number4
DOIs
StatePublished - Feb 15 2005
Externally publishedYes

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