title: A Truncated Granulocyte Colony-stimulating Factor Receptor (G-CSFR) Inhibits Apoptosis Induced by Neutrophil Elastase G185R Mutant: IMPLICATION FOR UNDERSTANDING CSF3R GENE MUTATIONS IN SEVERE CONGENITAL NEUTROPENIA.
abstract: Mutations inELANEencoding neutrophil elastase (NE) have been identified in the majority of patients with severe congenital neutropenia (SCN). The NE mutants have been shown to activate unfolded protein response and induce premature apoptosis in myeloid cells. Patients with SCN are predisposed to acute myeloid leukemia (AML), and progression from SCN to AML is accompanied by mutations inCSF3Rencoding the granulocyte colony-stimulating factor receptor (G-CSFR) in ∼80% of patients. The mutations result in the expression of C-terminally truncated G-CSFRs that promote strong cell proliferation and survival. It is unknown why theCSF3Rmutations, which are rare inde novoAML, are so prevalent in SCN/AML. We show here that a G-CSFR mutant, d715, derived from an SCN patient inhibited G-CSF-induced expression of NE in a dominant negative manner. Furthermore, G-CSFR d715 suppressed unfolded protein response and apoptosis induced by an SCN-derived NE mutant, which was associated with sustained activation of AKT and STAT5, and augmented expression of BCL-XL. Thus, the truncated G-CSFRs associated with SCN/AML may protect myeloid precursor cells from apoptosis induced by the NE mutants. We propose that acquisition ofCSF3Rmutations may represent a mechanism by which myeloid precursor cells carrying theELANEmutations evade the proapoptotic activity of the NE mutants in SCN patients.
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Yaling
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Yangyang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606.
authors.forename: Nan
authors.initials: N
authors.lastname: Hu
authors.affiliation: Department of Biological Sciences, University of Toledo, Toledo, Ohio 43606. Electronic address: fan.dong@utoledo.edu.
authors.forename: Fan
authors.initials: F
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D002460:Cell Line; D000080984:Congenital Bone Marrow Failure Syndromes; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism; D019272:Leukocyte Elastase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D009154:Mutation; D009503:Neutropenia / Q000151:congenital* / Q000235:genetics / Q000378:metabolism; D017354:Point Mutation; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics* / Q000378:metabolism; D056811:Unfolded Protein Response
chemical_list: C517047:CSF3R protein, human; D016184:Receptors, Colony-Stimulating Factor; D019272:Leukocyte Elastase
keywords: apoptosis; cell differentiation; cell surface receptor; leukemia; neutrophil