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.
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Acknowledgements
This work was supported by the German Research Foundation (DFG, Research priority program 1230 and cluster of excellence REBIRTH) and the European Union (grants Clinigene and CELL-PID). We thank Rena-Mareike Struss, Institute of Experimental Hematology, Hannover Medical School, Hannover, Germany, for help with breeding and genotyping of mice. We thank the Cell Sorting Unit of Hannover Medical School for support in sorting experiments. We are grateful to Marcel Tauscher, Institute of Cell and Molecular Pathology, Hannover Medical School, Hannover, Germany, for support in performing array-CGH analysis.
Author Contributions
OSK, MS, A Schwarzer, A Schambach, TCH, MHB, NH, DS, MY and ZL performed experiments. SG and IR performed mathematical modeling. All authors analyzed data. CB and OSK designed the study, and wrote the manuscript. A Schwarzer, MHB, NH, ZL, SG, DS, BS contributed to writing the manuscript.
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Kustikova, O., Schwarzer, A., Stahlhut, M. et al. Activation of Evi1 inhibits cell cycle progression and differentiation of hematopoietic progenitor cells. Leukemia 27, 1127–1138 (2013). https://doi.org/10.1038/leu.2012.355
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DOI: https://doi.org/10.1038/leu.2012.355
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