Here we show that mutations of Zrsr2 and Tet2, genes commonly co-mutated in human MDS, resulted in impairment of myelo-erythroid differentiation and the development of thrombocytopenia and anemia, multi-lineage dysplasia, and splenomegaly with extramedullary hematopoiesis. Here, ZRSR2 is linked to anemia (phenotype).