title: Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells.
abstract: The transcription factor Evi1 has an outstanding role in the formation and transformation of hematopoietic cells. Its activation by chromosomal rearrangement induces a myelodysplastic syndrome with progression to acute myeloid leukemia of poor prognosis. Similarly, retroviral insertion-mediated upregulation confers a competitive advantage to transplanted hematopoietic cells, triggering clonal dominance or even leukemia. To study the molecular and functional response of primary murine hematopoietic progenitor cells to the activation of Evi1, we established an inducible lentiviral expression system. EVI1 had a biphasic effect with initial growth inhibition and retarded myeloid differentiation linked to enhanced survival of myeloblasts in long-term cultures. Gene expression microarray analysis revealed that within 24 h EVI1 upregulated 'stemness' genes characteristic for long-term hematopoietic stem cells (Aldh1a1, Abca1, Cdkn1b, Cdkn1c, Epcam, among others) but downregulated genes involved in DNA replication (Cyclins and their kinases, among others) and DNA repair (including Brca1, Brca2, Rad51). Cell cycle analysis demonstrated EVI1's anti-proliferative effect to be strictly dose-dependent with accumulation of cells in G0/G1, but preservation of a small fraction of long-term proliferating cells. Although confined to cultured cells, our study contributes to new hypotheses addressing the mechanisms and molecular targets involved in preleukemic clonal dominance or leukemic transformation by Evi1.
authors.affiliation: Institute of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany.
authors.forename: O S
authors.initials: OS
authors.lastname: Kustikova
authors.forename: A
authors.initials: A
authors.lastname: Schwarzer
authors.forename: M
authors.initials: M
authors.lastname: Stahlhut
authors.forename: M H
authors.initials: MH
authors.lastname: Brugman
authors.forename: T
authors.initials: T
authors.lastname: Neumann
authors.forename: M
authors.initials: M
authors.lastname: Yang
authors.forename: Z
authors.initials: Z
authors.lastname: Li
authors.forename: A
authors.initials: A
authors.lastname: Schambach
authors.forename: N
authors.initials: N
authors.lastname: Heinz
authors.forename: S
authors.initials: S
authors.lastname: Gerdes
authors.forename: I
authors.initials: I
authors.lastname: Roeder
authors.forename: T C
authors.initials: TC
authors.lastname: Ha
authors.forename: D
authors.initials: D
authors.lastname: Steinemann
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: C
authors.initials: C
authors.lastname: Baum
mesh_terms: D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000502:physiology*; D042381:Granulocyte Precursor Cells / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D051379:Mice; D008810:Mice, Inbred C57BL; D011519:Proto-Oncogenes / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D014157:Transcription Factors