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Molecular Biology, Pathobiology and Genetics |
1 Divisions of Hematology-Oncology, Department of Internal Medicine and the Comprehensive Cancer Center, 2 Department of Veterinary Biosciences, and 3 Division of Human Cancer Genetics, Department of Molecular Virology Immunology and Medical Genetics, Ohio State University, Columbus, Ohio; and 4 Department of Molecular Pathology, University of Texas and MD Anderson Cancer Center, Houston, Texas
Requests for reprints: Guido Marcucci, Division of Hematology-Oncology, Ohio State University, 310 10th Avenue, Starling Loving Hall, Columbus, OH 43210. Phone: 614-293-9868; Fax: 614-293-7526; E-mail: marcucci-1{at}medctr.osu.edu.
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.
Key Words: Leukemias and lymphomas • Chromosomal translocations: genomic aspects • Molecular Oncology • DNA methylation/epigenetics • Chromatin structure/higher order regulation, acetylation
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