title: Novel mechanism of G-CSF refractoriness in patients with severe congenital neutropenia.
abstract: Severe congenital neutropenia (SCN) is a rare disease diagnosed at or soon after birth, characterized by a myeloid maturation arrest in the bone marrow, ineffective neutrophil production, and recurrent infections. Most patients respond to treatment with granulocyte colony-stimulating factor (G-CSF), and the majority harbor mutations in the neutrophil elastase gene. In the subset of patients with SCN transforming to acute myeloid leukemia (AML), mutations that truncate the cytoplasmic tail of the G-CSF receptor (G-CSFR) have been detected. Here, we report a novel mutation in the extracellular portion of the G-CSFR within the WSXWS motif in a patient with SCN without AML who was refractory to G-CSF treatment. The mutation affected a single allele and introduced a premature stop codon that deletes the distal extracellular region and the entire transmembrane and cytoplasmic portions of the G-CSFR. Expression of the mutant receptor in either myeloid or lymphoid cells was shown to alter subcellular trafficking of the wild-type (WT) G-CSFR by constitutively heterodimerizing with it. WT/mutant G-CSFR heterodimers appeared to be retained in the endoplasmic reticulum and/or Golgi and accumulate intracellularly. These findings together with 2 previous case reports of extracellular mutations in the G-CSFR in patients with SCN unresponsive to G-CSF suggest a common mechanism underlying G-CSF refractoriness.
authors.affiliation: Bone Marrow Transplant Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Lawrence J
authors.initials: LJ
authors.lastname: Druhan
authors.forename: Jing
authors.initials: J
authors.lastname: Ai
authors.forename: Pam
authors.initials: P
authors.lastname: Massullo
authors.forename: Tamila
authors.initials: T
authors.lastname: Kindwall-Keller
authors.forename: Mark A
authors.initials: MA
authors.lastname: Ranalli
authors.forename: Belinda R
authors.initials: BR
authors.lastname: Avalos
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D019281:Dimerization; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007231:Infant, Newborn; D008024:Ligands; D008297:Male; D009503:Neutropenia / Q000151:congenital / Q000188:drug therapy* / Q000235:genetics*; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010290:Parents; D017354:Point Mutation; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology
chemical_list: D008024:Ligands; D016188:Receptors, Granulocyte Colony-Stimulating Factor; D016179:Granulocyte Colony-Stimulating Factor