title: Kostmann syndrome: severe congenital neutropenia associated with defective expression of Bcl-2, constitutive mitochondrial release of cytochrome c, and excessive apoptosis of myeloid progenitor cells.
abstract: Kostmann syndrome, or severe congenital neutropenia (SCN), is an autosomal recessive disorder of neutrophil production. To investigate the potential role of apoptosis in SCN, bone marrow aspirates and biopsies were obtained from 4 patients belonging to the kindred originally described by Kostmann and 1 patient with SCN of unknown inheritance. An elevated degree of apoptosis was observed in the bone marrow of these patients, and a selective decrease in B-cell lymphoma-2 (Bcl-2) expression was seen in myeloid progenitor cells. Furthermore, in vitro apoptosis of bone marrow-derived Kostmann progenitor cells was increased, and mitochondrial release of cytochrome c was detected in CD34(+) and CD33(+) progenitors from patients, but not in controls. Administration of granulocyte colony-stimulating factor (G-CSF) restored Bcl-2 expression and improved survival of myeloid progenitor cells. In addition, cytochrome c release was partially reversed upon incubation of progenitor cells with G-CSF. In sum, these studies establish a role for mitochondria-dependent apoptosis in the pathogenesis of Kostmann syndrome and yield a tentative explanation for the beneficial effect of growth factor administration in these patients.
authors.affiliation: Childhood Cancer Research Center, Department of Woman and Child Health, Karolinska Hospital, Stockholm, Sweden.
authors.forename: Göran
authors.initials: G
authors.lastname: Carlsson
authors.forename: Andrew A G
authors.initials: AA
authors.lastname: Aprikyan
authors.forename: Ramin
authors.initials: R
authors.lastname: Tehranchi
authors.forename: David C
authors.initials: DC
authors.lastname: Dale
authors.forename: Anna
authors.initials: A
authors.lastname: Porwit
authors.forename: Eva
authors.initials: E
authors.lastname: Hellström-Lindberg
authors.forename: Jan
authors.initials: J
authors.lastname: Palmblad
authors.forename: Jan-Inge
authors.initials: JI
authors.lastname: Henter
authors.forename: Bengt
authors.initials: B
authors.lastname: Fadeel
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001853:Bone Marrow; D016022:Case-Control Studies; D002675:Child, Preschool; D045304:Cytochromes c / Q000378:metabolism; D005192:Family Health; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D023461:Myeloid Progenitor Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009503:Neutropenia / Q000151:congenital* / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000187:drug effects; D013577:Syndrome
chemical_list: D019253:Proto-Oncogene Proteins c-bcl-2; D016179:Granulocyte Colony-Stimulating Factor; D045304:Cytochromes c