Patients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML). In the subset of patients with SCN that progresses to AML, acquired mutations in the receptor for granulocyte colony-stimulating factor (G-CSF) have been detected that result in the expression of truncated forms of the G-CSF receptor (G-CSFR) protein. G-CSFR truncation mutants from these patients trans-duce hyperproliferative growth responses. In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (▵716) confers resistance to apoptosis and prolongs cell survival through a mechanism involving Akt, a downstream target of PI3-kinase. G-CSF stimulation of cells expressing the G-CSFR truncation mutant induces sustained activation of Akt and prolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enhanced cell survival. Extension of cell survival allowing for sufficient time for the acquisition of additional oncogenic events may represent an important mechanism by which G-CSFR mutations contribute to leukemogenesis. These data provide further insight into the pathophysiologic contribution of G-CSFR mutations to AML.