title: The MDS and EVI1 complex locus (MECOM) isoforms regulate their own transcription and have different roles in the transformation of hematopoietic stem and progenitor cells.
abstract: Transcriptional activation of the EVI1 oncogene (3q26) leads to aggressive forms of human acute myeloid leukemia (AML). However, the mechanism of EVI1-mediated leukemogenesis has not been fully elucidated. Previously, by characterizing the EVI1 promoter, we have shown that RUNX1 and ELK1 directly regulate EVI1 transcription. Intriguingly, bioinformatic analysis of the EVI1 promoter region identified the presence of several EVI1 potential binding sites. Thus, we hypothesized that EVI1 could bind to these sites regulating its own transcription. In this study, we show that there is a functional interaction between EVI1 and its promoter, and that the different EVI1 isoforms (EVI1-145kDa, EVI1-Δ324 and MDS1-EVI1) regulate the transcription of EVI1 transcripts through distinct promoter regions. Moreover, we determine that the EVI1-145kDa isoform activates EVI1 transcription, whereas EVI1-Δ324 and MDS1-EVI1 act as repressors. Finally, we demonstrate that these EVI1 isoforms are involved in cell transformation; functional experiments show that EVI1-145kDa prolongs the maintenance of hematopoietic stem and progenitor cells; conversely, MDS1-EVI1 repressed hematopoietic stem and progenitor colony replating capacity. We demonstrate for the first time that EVI1 acts as a regulator of its own expression, highlighting the complex regulation of EVI1, and open new directions to better understand the mechanisms of EVI1 overexpressing leukemias.
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain. Electronic address: mmaicas@ibv.csic.es.
authors.forename: Miren
authors.initials: M
authors.lastname: Maicas
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Iria
authors.initials: I
authors.lastname: Vázquez
authors.affiliation: School of Medicine and Research Institute "Dr. Viña Giner", Molecular and Mitochondrial Medicine, Catholic University of Valencia San Vicente Mártir, Valencia, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Alis
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Marcotegui
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Leire
authors.initials: L
authors.lastname: Urquiza
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Cortés-Lavaud
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: Ion
authors.initials: I
authors.lastname: Cristóbal
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain.
authors.forename: María A
authors.initials: MA
authors.lastname: García-Sánchez
authors.affiliation: Program of Hematology-Oncology, CIMA, University of Navarra, Pamplona, Spain; Department of Biochemistry and Genetics, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IDISNA), Spain.
authors.forename: María D
authors.initials: MD
authors.lastname: Odero
mesh_terms: D000818:Animals; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D011401:Promoter Regions, Genetic; D011519:Proto-Oncogenes / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; C499305:Mecom protein, mouse; D014157:Transcription Factors
keywords: Acute myeloid leukemia; EVI1; Isoforms; Promoter; Transcription factor