Background: Myelodysplastic syndrome (MDS) is a clonal disease of the elderly characterized by chronic cytopenia, dysplasia, and a high risk of progression to acute myeloid leukemia (AML). Up until now, few animal models that fully recapitulate clinical features of this disease have been available. Methods: This study aimed to establish a new MDS xenograft model utilizing a human MDS-derived cell line with heterozygous Y641C mutation of EZH2 (SKM-1). 1 x 10(7) SKM-1 cells were inoculated into anti-mouse CD122 monoantibody conditioned nonobese diabetic severe combined immunodeficiency (NOD/SCID) mice by intravenous injection. Decitabine was injected intraperitoneally for evaluation of epigenetic drugs in vivo. Results: It is shown that the heterozygous Y641C mutation in the EZH2 gene mutation, which may destabilize the protein ((Delta Delta)G = 1.46 kcal/mol), can be found in SKM-1 cells. Most mice presented anemia and leukopenia at three to four weeks after inoculation. The peripheral blood and bone marrow smear showed prominent dysplasia on erythrocytes and granulocytes as well as monocytes. Conclusions: These findings suggest that intravenous inoculation of cells from the human MDS-derived cell line prior to targeted depletion of CD122(+) cells could provide a novel MDS-like xenotransplant mouse model. It is a useful tool for evaluating potential existing and novel therapeutics for MDS.