The First Zinc Finger Domain of EVI1 Enhances Self-Renewal of Hematopoietic Progenitors.

Abstract

EVI1 was first identified as a preferential integration site of ecotropic retroviruses in the MDS1/EVI1 genomic locus leading to myeloid tumors in susceptible mice. Later studies showed that retroviral integration in the MDS1/EVI1 locus results in the emergence of a non-malignant dominant hematopoietic stem cell clone in non-susceptible mice strains, in non-human primates, and in patients, suggesting that a gene encoded by the locus could be deregulated by the retrovirus and affect the self-renewal potential of the cell. The locus encodes two genes. One of them, EVI1, has long been associated with myeloid leukemia and myelodysplastic syndrome. To understand whether EVI1 has a role in self-renewal control, we forcibly expressed EVI1 in the bone marrow progenitors of two mouse strains that differ in their proliferation and self-renewal potential. By comparing the response of the hematopoietic cells to EVI1, we show that EVI1 has a role in prolonging the self-renewal potential of the cells and that this ability of EVI1 is however limited and modulated by inherent strain-specific characteristics. To identify the region of EVI1 mediating this effect, we infected the bone marrow progenitors of the two murine strains with EVI1 wild type or with specific alternative EVI1 point mutants and compared the self-renewal potential of the cells. This approach allowed us to show that the first zinc finger domain of EVI1 is required to enhance the self-renewal of the hematopoietic progenitors. This function is mediated by two specific zinc finger motifs and their disruption by point mutations abolished this effect. These results suggest that the motifs interact with factors that regulate self-renewal. The cooperation between EVI1 and these unknown proteins in deregulation of self-renewal occurs inappropriately when EVI1 is deregulated, but based on EVI1 gene knock out studies it is likely that this function of EVI1 is required during embryonic development.