<i>ROBO1</i> deficiency impairs HSPC homeostasis and erythropoiesis via <i>CDC42</i> and predicts poor prognosis in MDS.

Abstract

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 (<i>ROBO1</i>) mutations in patients with MDS, while the exact role of <i>ROBO1</i> in hematopoiesis remains poorly delineated. Here, we report that <i>ROBO1</i> deficiency confers MDS-like disease with anemia and multilineage dysplasia in mice and predicts poor prognosis in patients with MDS. More specifically, <i>Robo1</i> 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 <i>Cdc42</i>, a member of the Rho-guanosine triphosphatase family, acts as a downstream target gene for <i>Robo1</i> in HSPCs. Overexpression of <i>Cdc42</i> partially restores the self-renewal and erythropoiesis of HSPCs in <i>Robo1</i>-deficient mice. Collectively, our result implicates the essential role of <i>ROBO1</i> in maintaining HSPC homeostasis and erythropoiesis via <i>CDC42</i>.