RhoH, a hematopoietic-specific Rho GTPase, regulates proliferation, survival, migration, and engraftment of hematopoietic progenitor cells

Abstract

Rho guanosine triphosphatases (GT-Pases) are recognized as critical mediators of signaling pathways regulating actin assembly, migration, proliferation, and survival in hematopoietic cells. Here, we have studied a recently identified hematopoietic-specific Rho GTPase, RhoH. Unlike most members of the Rho GTPase family, RhoH is GTPase deficient and does not cycle between GTP- and guanosine diphosphate (GDP)-bound forms, suggesting that regulation of RhoH expression may be critical in its activity. We found that RhoH is expressed in murine hematopoietic progenitor cells (HPCs) and fully differentiated myeloid and lymphoid lineages. In cytokine-stimulated HPCs, knockdown of RhoH expression via RNA interference stimulates proliferation, survival, and stromal cell-derived factor-1 alpha (SDF-1 alpha)-induced migration in vitro. Conversely, RhoH overexpression in these cells via retrovirus-mediated gene transfer is associated with impaired activation of Rac GTPases, reduced proliferation, increased apoptosis, and defective actin polymerization and chemotaxis. In vivo, HPCs with RhoH overexpression demonstrate defective hematopoietic reconstitution capability compared with control vector-transduced cells. Our results suggest that RhoH serves as a negative regulator of both growth and actin-based function of HPCs possibly via suppression of Rac-mediated signaling.

RhoH/TTF Negatively Regulates Leukotriene Production in Neutrophils

“…In contrast to these findings obtained in T cells, RhoH/TTF has been described as a negative regulator of proliferation and engraftment of hemopoietic progenitor cells, perhaps due to the induction of apoptosis in these cells (10). We did not observe differences in the kinetics of neutrophil apoptosis between wild-type and Rhoh Ϫ/Ϫ mice (data not shown).…”

Oncogenic Vav1 induces Rac-dependent apoptosis via inhibition of Bcl-2 family proteins and collaborates with p53 deficiency to promote hematopoietic progenitor cell proliferation

“…HSC/P is multipotent and capable to reconstitute hematopoiesis in lethally irradiated recipient mice. We next examined whether Vav1D180 affects engraftment and reconstitution of HSC/Ps using a competitive engraftment assay (Gu et al, 2005). A mixture of 2 Â 10 5 transduced EGFP þ bone marrow (BM) cells and 8 Â 10 5 untransduced EGFP À competitor BM cells was injected intravenously into lethally irradiated congenic recipient mice.…”

Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment

“…by guest www.bloodjournal.org From the cells. 31 It is anticipated that individual members of the Rho family may contribute uniquely to hematopoiesis.…”