title: A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome.
abstract: The granulocyte colony-stimulating factor receptor (G-CSF-R) transmits signals for proliferation and differentiation of myeloid progenitor cells. Here we report on the identification of a rare single nucleotide polymorphism within its intracellular domain (G-CSF-R_Glu785Lys). Screening a cohort of 116 patients with primary myelodysplastic syndromes (MDS), de novo acute myeloid leukemia (AML) (84 patients), as well as 232 age- and sex-matched controls revealed a highly significant association of the G-CSF-R_785Lys allele with the development of high-risk MDS as defined by more than 5% bone marrow blasts (9.7% versus 0.9% in controls; P = .001; odds ratio [OR], 12.5; 95% confidence interval [CI], 2.4-58.9) or an International Prognostic Scoring System score of intermediate-2 or high (13.0% versus 0.9%; P < .001; OR, 14.0; 95% CI, 3.4-85.0). Functional analysis by retroviral transfer of G-CSF-R_785Lys into myeloid progenitor cells of G-CSF-R-deficient mice showed a significantly diminished colony-formation capacity after G-CSF stimulation as compared with cells transduced with the wild-type receptor. These results suggest that lifelong altered G-CSF response by the G-CSF-R_785Lys may render individuals susceptible to development of high-risk MDS.
authors.affiliation: Division of Hematology, Medical University of Graz, Auenbruggerplatz 38, A-8036 Graz, Austria.
authors.forename: Albert
authors.initials: A
authors.lastname: Wölfler
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Erkeland
authors.forename: Claudia
authors.initials: C
authors.lastname: Bodner
authors.forename: Marijke
authors.initials: M
authors.lastname: Valkhof
authors.forename: Wilfried
authors.initials: W
authors.lastname: Renner
authors.forename: Christina
authors.initials: C
authors.lastname: Leitner
authors.forename: Werner
authors.initials: W
authors.lastname: Olipitz
authors.forename: Michael
authors.initials: M
authors.lastname: Pfeilstöcker
authors.forename: Christoph
authors.initials: C
authors.lastname: Tinchon
authors.forename: Werner
authors.initials: W
authors.lastname: Emberger
authors.forename: Werner
authors.initials: W
authors.lastname: Linkesch
authors.forename: Ivo P
authors.initials: IP
authors.lastname: Touw
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D002478:Cells, Cultured; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006412:Hematopoietic Stem Cells; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D023461:Myeloid Progenitor Cells / Q000378:metabolism / Q000637:transplantation; D020641:Polymorphism, Single Nucleotide; D016188:Receptors, Granulocyte Colony-Stimulating Factor / Q000235:genetics*; D012306:Risk; D014161:Transduction, Genetic; D014162:Transfection
chemical_list: D016188:Receptors, Granulocyte Colony-Stimulating Factor