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

Biochim Biophys Acta Gene Regul Mech. 2017 Jun;1860(6):721-729. doi: 10.1016/j.bbagrm.2017.03.007. Epub 2017 Apr 6.

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.

Keywords: Acute myeloid leukemia; EVI1; Isoforms; Promoter; Transcription factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Gene Expression Regulation, Leukemic*
  • Hematopoietic Stem Cells / metabolism*
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia / genetics
  • Leukemia / metabolism*
  • Leukemia / pathology
  • MDS1 and EVI1 Complex Locus Protein
  • Mice
  • Promoter Regions, Genetic*
  • Proto-Oncogenes / genetics
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • DNA-Binding Proteins
  • MDS1 and EVI1 Complex Locus Protein
  • MECOM protein, human
  • Mecom protein, mouse
  • Transcription Factors