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Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells.
MedLine Citation:
PMID:  23212151     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
The transcription factor Evi1 plays 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 down-regulated 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 G(0)/G(1), 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.Leukemia accepted article preview online, 5 December 2012; doi:10.1038/leu.2012.355.
Authors:
O S Kustikova; A Schwarzer; M Stahlhut; M H Brugman; T Neumann; M Yang; Z Li; A Schambach; N Heinz; S Gerdes; I Roeder; T C Ha; D Steinemann; B Schlegelberger; C Baum
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-12-05
Journal Detail:
Title:  Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K     Volume:  -     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-5     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany.
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