ROBO1 deficiency impairs HSPC homeostasis and erythropoiesis via CDC42 and predicts poor prognosis in MDS

Myelodysplastic syndrome (MDS) is a group of clonal hematopoietic neoplasms originating from hematopoietic stem progenitor cells (HSPCs). We previously identified frequent roundabout guidance receptor 1 ( ) mutations in patients with MDS, while the exact role of in hematopoiesis remains poorly delineated. Here, we report that deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, deficiency impairs HSPC homeostasis and disrupts HSPC pool, especially the reduction of megakaryocyte erythroid progenitors, which causes a blockage in the early stages of erythropoiesis in mice. Mechanistically, transcriptional profiling indicates that , a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for in HSPCs. Overexpression of partially restores the self-renewal and erythropoiesis of HSPCs in -deficient mice. Collectively, our result implicates the essential role of in maintaining HSPC homeostasis and erythropoiesis via .