Loss of RhoB expression enhances the myelodysplastic phenotype of mammalian diaphanous-related formin mDia1 knockout mice

Abstract

Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis and hyperplastic bone marrow. Complete loss or interstitial deletions of the long arm of chromosome 5 occur frequently in MDS. One candidate tumor suppressor on 5q is the mammalian Diaphanous (mDia)-related formin mDia1, encoded by DIAPH1 (5q31.3). mDia-family formins act as effectors for Rho-family small GTP-binding proteins including RhoB, which has also been shown to possess tumor suppressor activity. Mice lacking the Drf1 gene that encodes mDia1 develop age-dependent myelodysplastic features. We crossed mDia1 and RhoB knockout mice to test whether the additional loss of RhoB expression would compound the myelodysplastic phenotype. Drf1-/-RhoB-/- mice are fertile and develop normally. Relative to age-matched Drf1-/-RhoB+/- mice, the age of myelodysplasia onset was earlier in Drf1-/-RhoB-/- animals -including abnormally shaped erythrocytes, splenomegaly, and extramedullary hematopoiesis. In addition, we observed a statistically significant increase in the number of activated monocytes/macrophages in both the spleen and bone marrow of Drf1-/-RhoB-/- mice relative to Drf1-/-RhoB+/- mice. These data suggest a role for RhoB-regulated mDia1 in the regulation of hematopoietic progenitor cells. © 2009 DeWard et al.