Loss of FGFR3 accelerates bone marrow suppression-induced hematopoietic stem and progenitor cell expansion by activating FGFR1-ELK1-Cyclin D1 signaling.

Abstract Patients with chemotherapy or radiation therapy often generate anemia and low immunity due to the therapy-induced bone marrow (BM) suppression. To enhance hematopoietic regeneration during the disease treatment urgently need to be solved. Fibroblast growth factors (FGFs) play important regulatory roles in hematopoietic stem and progenitor cell (HSPC) expansion in vitro and in vivo by FGF receptor (FGFR1-4)-mediated signaling pathway. FGFR3 is an important member of FGFR family and its regulatory function in hematopoiesis is largely unknown. Using knock out (KO) mice of FGFR3, we found that loss of FGFR3 does not affect HSPC functions, linage differentiation during steady-state hematopoiesis, but FGFR3 deletion accelerates HSPC expansion and hematopoiesis recovery via a cell-autonomous manner under 5-FU-induced BM suppression. Our results showed that FGFR3 inactivation accelerates BM suppression-induced HSPC expansion by upregulating FGFR1 and its downstream transcriptional factor, ELK, which regulates the expression of Cyclin D1 gene at the level of transcription. Further studies confirmed that loss of FGFR3 in hematopoietic cells inhibits in vivo leukemogenesis under BM suppression. Our data firstly found a novel hematopoietic regulatory mechanism by which FGFR3 deletion promotes HSPC expansion under BM suppression, and also provided a promising approach to enhance anti-leukemia and hematopoietic regeneration by inhibiting FGFR3 functions in HSPCs combined with leukemic chemotherapy.