Two Point Mutations in the MDS-Associated Protein EVI1 Abrogate the Onset of MDS in the Mouse

By forcibly expressing EVI1 in murine bone marrow (BM) we previously generated a model for myelodysplastic syndrome (MDS) characterized by megakaryocytic hyperplasia, dysplastic erythropoiesis and fatal anemia. These defects, typical of MDS patients, confirmed the association between EVI1 and MDS in the mouse thus validating our mouse model. We later ascribed the erythroid defects induced by EVI1 to its interaction with GATA1, as shown by the double point mutant EVI1(1+6Mut), unable to bind GATA1, allowing a normal erythroid differentiation of BM progenitors in vitro. We report here that in vivo expression of the mutant EVI1(1+6Mut) abrogates the onset of MDS. We show that whereas EVI1-positive mice invariably die of severe anemia and pancytopenia 11–14 months after BM reconstitution, EVI1(1+6Mut)-positive mice maintained relatively normal erythropoiesis and blood counts until the study was terminated 20 months after BM transplantation. Furthermore, unlike the EVI1-positive mice two GATA1-regulated genes, EpoR and c-Mpl, are not repressed in the BM of the EVI1(1+6Mut)-mice. The normal expression of EpoR restores the response to Epo, in vitro, of the BM cells isolated from the EVI1(1+6Mut)-mice. We thus suggest that the development of drugs interfacing with the first and sixth zinc-finger motifs could be invaluable in the treatment of EVI1-positive MDS patients.