title: Global Identification of EVI1 Target Genes in Acute Myeloid Leukemia.
abstract: The ecotropic virus integration site 1 (EVI1) transcription factor is associated with human myeloid malignancy of poor prognosis and is overexpressed in 8-10% of adult AML and strikingly up to 27% of pediatric MLL-rearranged leukemias. For the first time, we report comprehensive genomewide EVI1 binding and whole transcriptome gene deregulation in leukemic cells using a combination of ChIP-Seq and RNA-Seq expression profiling. We found disruption of terminal myeloid differentiation and cell cycle regulation to be prominent in EVI-induced leukemogenesis. Specifically, we identified EVI1 directly binds to and downregulates the master myeloid differentiation gene Cebpe and several of its downstream gene targets critical for terminal myeloid differentiation. We also found EVI1 binds to and downregulates Serpinb2 as well as numerous genes involved in the Jak-Stat signaling pathway. Finally, we identified decreased expression of several ATP-dependent P2X purinoreceptors genes involved in apoptosis mechanisms. These findings provide a foundation for future study of potential therapeutic gene targets for EVI1-induced leukemia.
authors.affiliation: Department of Pathology and Lab Medicine, University of Rochester Medical Center, Rochester, New York, United States of America.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Glass
authors.forename: Charles
authors.initials: C
authors.lastname: Wuertzer
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Cui
authors.forename: Yingtao
authors.initials: Y
authors.lastname: Bi
authors.forename: Ramana
authors.initials: R
authors.lastname: Davuluri
authors.forename: Ying-Yi
authors.initials: YY
authors.lastname: Xiao
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.forename: Kristina
authors.initials: K
authors.lastname: Owens
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.forename: Archibald
authors.initials: A
authors.lastname: Perkins
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D017396:Plasminogen Activator Inhibitor 2 / Q000378:metabolism; D011519:Proto-Oncogenes / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D017396:Plasminogen Activator Inhibitor 2; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D014157:Transcription Factors; C070790:CEBPE protein, human; D053612:Janus Kinases