A complex in vivo model (transplantation of bone marrow (BM) cells from 8–12-week-old Cre-ERT;Ezh2fl/fl CD45.2 mice into lethally irradiated CD45.1 recipient mice and deletion of Ezh2 at 6 to 8 weeks posttransplantation) reveals that complete lack of EZH2 activity in hematopoietic stem cells (HSCs) predisposed mice to heterogenous malignancies (MDS, MDS/MPN, MDS/MPN associated with trombocytosis, and T cell acute lymphoblastic leukemia). The gene discussed is ELF3; the disease is myelodysplastic syndrome.