FET family proto-oncogene Fus contributes to self-renewal of hematopoietic stem cells

ObjectiveFus is the gene for a member of the FET family of RNA-binding proteins often involved in chromosomal translocations to generate oncogenic fusion genes in human cancers. Fus participates in multiple cellular functions, including RNA processing and transport, transcriptional regulation, and genome integrity. However, its role in hematopoiesis remains obscure. In this study, we examined its role in the self-renewal of hematopoietic stem cells (HSCs).Materials and MethodsHSCs in Fus−/− fetal livers were analyzed for proliferative capacity in vitro and long-term repopulating capacity in recipient mice. Radiation sensitivity of Fus−/− HSCs was evaluated in recipient mice repopulated by Fus−/− fetal liver cells.ResultsFus−/− fetal livers developed normally, except for a mild reduction in numbers of hematopoietic stem and progenitor cells compared to wild-type. The proliferation and differentiation of Fus−/− hematopoietic progenitors were normal in vitro. However, the number of colony-forming cells present in long-term cocultures of Fus−/− hematopoietic progenitors and stromal cells was significantly reduced. Fus−/− HSCs had an impaired long-term repopulating capacity and failed to repopulate in tertiary recipient mice. Fus−/− HSCs were highly susceptible to radiation both in vitro and in vivo and showed retardation of radiation-induced DNA damage repair.ConclusionOur findings define Fus as a novel regulator of self-renewal and radioprotection of HSCs and also implicate it in stress-resistance and maintenance of the genomic integrity of HSCs.