The transcription factor Gfi1 regulates G-CSF signaling and neutrophil development through the Ras activator RasGRP1

2 The transcription factor Gfi1 and the growth factor G-CSF are individually essential for neutrophil differentiation from myeloid progenitors, since mutant mice lacking Gfi1 or G-CSF/G-CSF receptor are severely neutropenic. Here, we provide evidence that the functions of Gfi1 and G-CSF are linked in the regulation of granulopoiesis. We report that Gfi1 promotes the expression of RasGRP1, an exchange factor that activates Ras, and that RasGRP1 is required for G-CSF signaling through the Ras/MEK/Erk pathway. Gfi1-null mice have reduced levels of RasGRP1 mRNA and protein in thymus, spleen, and bone marrow, and Gfi1 transduction in myeloid cells promotes RasGRP1 expression. When stimulated with G-CSF, Gfi1-null myeloid cells are selectively defective at activating Erk1/2, but not STAT1 or STAT3, and fail to differentiate into neutrophils. Expression of RasGRP1 in Gfi1-deficient cells rescues Erk1/2 activation by G-CSF and allows neutrophil maturation by G-CSF. These results uncover a previously unknow