||Inactivating somatic mutations in polycomb-group (PcG) genes, such as EZH2 and ASXL1, occur frequently in patients with myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), and MDS/MPN overlap disorders. Here we show that hematopoietic-restricted deletion of Ezh2 recapitulates MDS/MPN in mice. PcG gene mutations appeared to often coincide with tet methylcytosine dioxygenase 2 (TET2) mutations, and concurrent depletion of Ezh2 and Tet2 markedly accelerated development of MDS and MDS/MPN in mice. Upon deletion of Ezh2, PcG targets which lost H3K27me3 mark tended to acquire de novo DNA methylation while the bivalent genes were kept transcriptionally repressed via compensatory action of Ezh1. These findings establish the tumor repressor function of EZH2 and provide the first evidence of synergistic effects of the concurrent gene mutations in the pathogenesis of myelodysplasia.