A functional single-nucleotide polymorphism of the G-CSF receptor gene predisposes individuals to high-risk myelodysplastic syndrome

• Published in: Blood 2005-05, Vol.105 (9), p.3731-3736
• Main Authors: Wölfler, Albert, Erkeland, Stefan J., Bodner, Claudia, Valkhof, Marijke, Renner, Wilfried, Leitner, Christina, Olipitz, Werner, Pfeilstöcker, Michael, Tinchon, Christoph, Emberger, Werner, Linkesch, Werner, Touw, Ivo P., Sill, Heinz
• Format: Article
• Language: English
• Subjects: Acute Disease; Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Case-Control Studies; Cells, Cultured; Female; Genetic Predisposition to Disease; Genetic Testing; Hematologic and hematopoietic diseases; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid - genetics; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Mice; Mice, Knockout; Middle Aged; Myelodysplastic Syndromes - etiology; Myelodysplastic Syndromes - genetics; Myelodysplastic Syndromes - pathology; Myeloid Progenitor Cells - metabolism; Myeloid Progenitor Cells - transplantation; Polymorphism, Single Nucleotide; Receptors, Granulocyte Colony-Stimulating Factor - genetics; Risk; Transduction, Genetic; Transfection
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-06-2094

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.