title: Fadd and Skp2 are possible downstream targets of RUNX1-EVI1.
abstract: RUNX1-EVI1 generated by t(3;21) is a causative gene in the leukemic transformation of chronic hematopoietic stem cell tumors. Recruitment of histone deacetylase via carboxyl terminal-binding protein by RUNX1-EVI1 results in transcriptional dysregulation in target genes of wild-type RUNX1, leading to differentiation block and apoptotic prevention of myeloid precursor cells. In the present study using mouse primary hematopoietic cells, we confirmed that RUNX1-EVI1 enhances replating activity of hematopoietic colonies and represses differentiation along the myeloid lineage under treatment with granulocyte colony-stimulating factor. We then observed that these biological effects of RUX1-EVI1 are canceled by the treatment of histone deacetylase inhibitors, trichostatin A and valproic acid. To identify target genes whose expression is suppressed by RUNX1-EVI1, we compared the expression profiles of apoptosis and cell-cycle-related genes in control and RUNX1-EVI1-expressing cells, and in RUNX1-EVI1-expressing cells with and without treatment with histone deacetylase inhibitors. Notably, the expression of three genes, Fadd, Skp2 and CD40lg, was found to be suppressed in RUNX1-EVI1-expressing cells and to be recovered on treatment with histone deacetylase inhibitors. Considering that these genes have some RUNX1-binding sites, they may be direct or indirect targets of RUNX1-EVI1, and changes in their expression may play some role in leukemogenesis by RUNX1-EVI1.
authors.affiliation: Department of Hematology and Oncology, Dokkyo Medical University School of Medicine, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Maki
authors.forename: Fusako
authors.initials: F
authors.lastname: Sugita
authors.forename: Yuka
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Ko
authors.initials: K
authors.lastname: Sasaki
authors.forename: Kinuko
authors.initials: K
authors.lastname: Mitani
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D053200:Fas-Associated Death Domain Protein / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics*; D044786:S-Phase Kinase-Associated Proteins / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D053200:Fas-Associated Death Domain Protein; D056572:Histone Deacetylase Inhibitors; D000074008:MDS1 and EVI1 Complex Locus Protein; C499305:Mecom protein, mouse; D015514:Oncogene Proteins, Fusion; D044786:S-Phase Kinase-Associated Proteins; D014157:Transcription Factors