title: RUNX1 regulates corepressor interactions of PU.1.
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.
authors.affiliation: Department of Translational Hematology & Oncology Research, Taussig Cancer Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA.
authors.forename: Zhenbo
authors.initials: Z
authors.lastname: Hu
authors.forename: Xiaorong
authors.initials: X
authors.lastname: Gu
authors.forename: Kristine
authors.initials: K
authors.lastname: Baraoidan
authors.forename: Vinzon
authors.initials: V
authors.lastname: Ibanez
authors.forename: Arun
authors.initials: A
authors.lastname: Sharma
authors.forename: ShriHari
authors.initials: S
authors.lastname: Kadkol
authors.forename: Reinhold
authors.initials: R
authors.lastname: Munker
authors.forename: Steven
authors.initials: S
authors.lastname: Ackerman
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Nucifora
authors.forename: Yogen
authors.initials: Y
authors.lastname: Saunthararajah
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D046228:Microarray Analysis; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D000099232:Proto-Oncogene Protein Spi-1
chemical_list: D056970:Co-Repressor Proteins; D050676:Core Binding Factor Alpha 2 Subunit; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099232:Proto-Oncogene Protein Spi-1; C493728:RUNX1 protein, human