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

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 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 >5% bone marrow blasts (9.7% vs. 0.9% in controls; p=0.001; odds ratio (OR) 12.5, 95% CI 2.4-58.9) or an international prognostic score of intermediate-2 or high (13.0% vs. 0.9%; p<0.001; 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 to cells transduced with the wildtype 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.From bloodjournal.hematologylibrary.org by guest on September 29, 2012. For personal use only.