Fadd and Skp2 are possible downstream targets of RUNX1-EVI1

• Published in: International journal of hematology Vol. 97; no. 1; pp. 83 - 91
• Main Authors: Maki, Kazuhiro, Sugita, Fusako, Nakamura, Yuka, Sasaki, Ko, Mitani, Kinuko
• Format: Journal Article
• Language: English
• Published: Japan Springer Japan 01.01.2013; Springer; Springer Nature B.V
• Subjects: Animals; Biological and medical sciences; Bone Marrow Cells - cytology; Bone Marrow Cells - drug effects; Bone Marrow Cells - metabolism; Cell Differentiation - drug effects; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells, Cultured; Core Binding Factor Alpha 2 Subunit - genetics; DNA-Binding Proteins - genetics; Fas-Associated Death Domain Protein - genetics; Gene Expression Regulation - drug effects; Hematologic and hematopoietic diseases; Hematology; Hematopoietic Stem Cells - cytology; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - metabolism; Histone Deacetylase Inhibitors - pharmacology; MDS1 and EVI1 Complex Locus Protein; Medical sciences; Medicine; Medicine & Public Health; Mice; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncology; Original Article; Proto-Oncogenes - genetics; S-Phase Kinase-Associated Proteins - genetics; Transcription Factors - genetics; Target genes; Leukemogenesis; Histone deacetylase inhibitor; RUNX1-EVI1; RUNX1; Targeting; Hematology; Fas associated death domain protein; Genetics; Adaptor protein; Carcinogenesis; RUNX1 gene
• ISSN: 0925-5710; 1865-3774
• DOI: 10.1007/s12185-012-1232-5

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.