title: Granulocyte colony-stimulating factor receptor mutations in severe congenital neutropenia transforming to acute myelogenous leukemia confer resistance to apoptosis and enhance cell survival.
abstract: 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 transduce hyperproliferative growth responses. In this paper, we show that the most frequently isolated mutant G-CSFR form from patients with SCN/AML (delta716) 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. (Blood. 2000;95:2132-2137)
authors.affiliation: Molecular, Cellular, and Developmental Biology Program and the Bone Marrow Transplantation Program, The Ohio State University, Arthur G. James Cancer Hospital & Research Institute, Columbus, OH 43210, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hunter
authors.forename: B R
authors.initials: BR
authors.lastname: Avalos
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D004789:Enzyme Activation; D016179:Granulocyte Colony-Stimulating Factor / Q000502:physiology*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D051379:Mice; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D051025:bcl-Associated Death Protein
chemical_list: D002352:Carrier Proteins; D016179:Granulocyte Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D011994:Recombinant Proteins; D051025:bcl-Associated Death Protein; C494820:Bad protein, mouse