title: 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.
authors.affiliation: Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, Michigan, United States of America.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: DeWard
authors.forename: Kellie
authors.initials: K
authors.lastname: Leali
authors.forename: Richard A
authors.initials: RA
authors.lastname: West
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Alberts
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D005326:Fetal Proteins / Q000378:metabolism*; D000080865:Formins; D005786:Gene Expression Regulation; D006412:Hematopoietic Stem Cells / Q000166:cytology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000378:metabolism*; D009000:Monocytes / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism*; D010641:Phenotype; D013154:Spleen / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000096:biosynthesis* / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; C491464:Diap1 protein, mouse; D005326:Fetal Proteins; D000080865:Formins; D008840:Microfilament Proteins; D009687:Nuclear Proteins; D020743:rhoB GTP-Binding Protein