RUNX1 regulates corepressor interactions of PU.1
Open Access
- 16 June 2011
- journal article
- Published by American Society of Hematology in Blood
- Vol. 117 (24), 6498-6508
- https://doi.org/10.1182/blood-2010-10-312512
Abstract
The transcription factor (TF) RUNX1 cooperates with lineage-specifying TFs (eg, PU.1/SPI1) to activate myeloid differentiation genes, such as macrophage and granulocyte macrophage colony-stimulating factor receptors (MCSFR and GMCSFR). Disruption of cooperative gene activation could contribute to aberrant repression of differentiation genes and leukemogenesis initiated by mutations and translocations of RUNX1. To investigate the mechanisms underlying cooperative gene activation, the effects of Runx1 deficiency were examined in an in vitro model of Pu.1-driven macrophage differentiation and in primary cells. Runx1 deficiency decreased Pu.1-mediated activation of Mcsfr and Gmcsfr, accompanied by decreased histone acetylation at the Mcsfr and Gmcsfr promoters, and increased endogenous corepressor (Eto2, Sin3A, and Hdac2) coimmunoprecipitation with Pu.1. In cotransfection experiments, corepressors were excluded from a multiprotein complex containing full-length RUNX1 and PU.1. However, corepressors interacted with PU.1 if wild-type RUNX1 was replaced with truncated variants associated with leukemia. Histone deacetylase (HDAC) enzyme activity is a major component of corepressor function. HDAC inhibition using suberoylanilide hydroxamic acid or MS-275 significantly increased MCSFR and GMCSFR expression in leukemia cell lines that express PU.1 and mutated or translocated RUNX1. RUNX1 deficiency is associated with persistent corepressor interaction with PU.1. Thus, inhibiting HDAC can partly compensate for the functional consequences of RUNX1 deficiency.This publication has 50 references indexed in Scilit:
- Decitabine Maintains Hematopoietic Precursor Self-Renewal by Preventing Repression of Stem Cell Genes by a Differentiation-Inducing StimulusMolecular Cancer Therapeutics, 2010
- Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemiaProceedings of the National Academy of Sciences of the United States of America, 2009
- Differentiation-Dependent Interactions between RUNX-1 and FLI-1 during Megakaryocyte DevelopmentMolecular and Cellular Biology, 2009
- Differentiation therapy of leukemia: 3 decades of developmentBlood, 2009
- Oct-1 Maintains an Intermediate, Stable State of HLA-DRA Promoter Repression in Rb-defective CellsPublished by Elsevier BV ,2004
- Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1Nature Genetics, 2004
- Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repressionOncogene, 2003
- In vivo complex formation of PU.1 with HDAC1 associated with PU.1-mediated transcriptional repressionOncogene, 2001
- Physical and functional interactions between the transcription factor PU.1 and the coactivator CBPOncogene, 1999
- Recruitment of CBP/p300 by the IFNβ Enhanceosome Is Required for Synergistic Activation of TranscriptionMolecular Cell, 1998