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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2005-02, Vol.65 (4), p.1277-1284
• Main Authors: SHUJUN LIU, TIANSHENG SHEN, VUKOSAVLJEVIC, Tamara, WHITMAN, Susan P, CHANG, Kun-Sang, BYRD, John C, PERROTTI, Danilo, PLASS, Christoph, MARCUCCI, Guido, LENGUYEN HUYNH, KLISOVIC, Marko I, RUSH, Laura J, FORD, Jamie L, JIANHUA YU, BECKNELL, Brian, YU LI, CHUNHUI LIU
• Format: Article
• Language: English
• Subjects: Acute Disease; Antineoplastic agents; Biological and medical sciences; Cell Line; Cell Line, Tumor; Core Binding Factor Alpha 2 Subunit; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-Binding Proteins - physiology; Gene Expression Regulation, Neoplastic - physiology; Gene Silencing; Hematologic and hematopoietic diseases; Humans; Interleukin-3 - genetics; Leukemia, Myeloid - enzymology; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical sciences; Pharmacology. Drug treatments; Promoter Regions, Genetic; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins - physiology; RUNX1 Translocation Partner 1 Protein; Transcription Factors - genetics; Transcription Factors - metabolism; Transcription Factors - physiology; Transcription, Genetic - physiology; Transfection
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-04-4532

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.