Myeloproliferative defects following targeting of the Drf1 gene encoding the mammalian diaphanous-related formin mDia1

Rho GTPase-effector mammalian diaphanous (mDia)-related formins assemble nonbranched actin filaments as part of cellular processes, including cell division, filopodia assembly, and intracellular trafficking. Whereas recent efforts have led to thorough characterization of formins in cytoskeletal remodeling and actin assembly in vitro, little is known about the role of mDia proteins in vivo. To fill this knowledge gap, the Drf1 gene, which encodes the canonical formin mDial, was targeted by homologous recombination. Upon birth, Drf1(+/-) and Drf1(-/-) mice were developmentally and morphologically indistinguishable from their wild-type littermates. However, both Drf1(+/-) and Drf1(-/-) developed age-dependent myeloproliferative defects. The phenotype included splenomegaly, fibrotic and hypercellular bone marrow, extramedullary hematopoiesis in both spleen and liver, and the presence of immature myeloid progenitor cells with high nucleus-to-cytoplasm ratios. Analysis of cell surface markers showed an age-dependent increase in the percentage of CD11b(+)-activated and CD14(+)-activated monocytes/macrophages in both spleen and bone marrow in Drf1(+/-) and Drf1(-/-) animals. Analysis of the erythroid compartment showed a significant increase in the proportion of splenic cells in S phase and an expansion of erythroid precursors (TER-119(+) and CD71(+)) in Drf1-targeted mice. Overall, knocking out mDial expression in mice leads to a phenotype similar to human myeloproliferative syndrome (MPS) and myelodysplastic syndromes (MDS). These observations suggest that defective DRF1 expression or mDial function may contribute to myeloid malignancies and point to mDial as an attractive therapeutic target in MDS and MPS.