Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival

patients with severe congenital neutropenia (SCN) are at increased risk for the development of acute myelogenous leukemia (AML), In the subset of pati ents with SCN that progresses to AML, acquired mutations in the receptor fo r granulocyte colony-stimulating factor (G-CSF) have been detected that res ult in the expression of truncated forms of the G-CSF receptor (G-CSFR) pro tein. G-CSFR truncation mutants from these patients transduce hyperprolifer ative growth responses, In this paper, we show that the most frequently iso lated mutant G-CSFR form from patients with SCN/AML (Delta 716) confers res istance to apoptosis and prolongs cell survival through a mechanism involvi ng AM, a downstream target of PI3-kinase. G-CSF stimulation of cells expres sing the G-CSFR truncation mutant induces sustained activation of Akt and p rolonged phosphorylation of the pro-apoptotic protein Bad, resulting in enh anced cell survival. Extension of cell survival allowing for sufficient tim e for the acquisition of additional oncogenic events may represent an impor tant mechanism by which G-CSFR mutations contribute to leukemogenesis, Thes e data provide further insight Into the pathophysiologic contribution of G- CSFR mutations to AML, (C) 2000 by The American Society of Hematology.