Abstract
The genetics responsible for the inter-individually variable G-CSF responsiveness remain elusive. A single nucleotide polymorphism (SNP) in the 3’UTR of CXCL12, rs1801157, was implicated in X4-tropic HiV susceptibility and later, in two small studies, in G-CSR responsiveness in patients and donors. The position of the SNP in the 3’UTR together with in-silico predictions suggested differential binding of micro-RNA941 as an underlying mechanism. In a cohort of 515 healthy stem cell donors we attempted to reproduce the correlation of the CXCL12 3’UTR SNP and mobilization responses and tested the role of miR941 in this context. The SNP was distributed with the expected frequency. Mobilization efficiency for CD34+ cells in WT, heterozygous and homozygous SNP individuals was indistinguishable, even after controlling for gender. miR941 expression in non-hematopoietic bone marrow cells was undetectable and miR941 did not interact with the 3’ UTR of CXCL12. Proposed effects of the SNP rs1801157 on G-CSF responsiveness cannot be confirmed in a larger cohort.
Highlights
Allogeneic G-CSF mobilized peripheral blood stem/progenitor cells from healthy volunteer donors have become the source of choice for allogeneic “stem cell” transplantation.[1,2,3] A hundred-fold difference in G-CSF responsiveness between poorly and well mobilizing donors was noticed early on, but except for an arguable, if anything weak effect of gender no predictors of mobilization response have been identified.[4,5,6] Several examples suggest that mobilization response is genetically determined: Humans subjected to successive cycles of G-CSF respondedPLOS ONE | DOI:10.1371/journal.pone.0121859 March 24, 2015single nucleotide polymorphism (SNP) rs1801157 and Mobilization Efficiency
Three small studies on autologous donors or healthy volunteer donors suggested a correlation between a single-nucleotide polymorphism (SNP) in the 3’URT of CXCL12ß, rs1801157, and G-CSF mobilization efficiency, which promised to be a break-through discovery in this field.[9,10,11]
Mobilization data were sorted by 3’UTR genotype and gender. miR941 expression in non-hematopoietic bone marrow (BM) stroma cells was tested in 20 anonymized CD45-purged BM samples from healthy volunteer donors using miR expression arrays (Miltenyi Biotec, Bergisch Gladbach, Germany) and taqMan qPCR. miR941 binding to the WT- or SNP variant CXCL12 3’UTR was tested by cloning premiR941 (Eurofins, Hamburg, Germany) or SNP-premiR941 (premiR941 mutated in the 4th position of the seed by site directed mutagenesis (Agilent technologies, Böblingen, Germany), to match the sequence of the SNP) into plasmid pSUPER.retro.puro (Oligoengine, Seattle, WA) and cloning of the whole 3’UTR of WT or SNP CXCL12ß (3285 bp) into the dual-luciferase plasmid pmirGLO (Promega, Mannheim, Germany)
Summary
Allogeneic G-CSF mobilized peripheral blood stem/progenitor cells from healthy volunteer donors have become the source of choice for allogeneic “stem cell” transplantation.[1,2,3] A hundred-fold difference in G-CSF responsiveness between poorly and well mobilizing donors was noticed early on, but except for an arguable, if anything weak effect of gender no predictors of mobilization response have been identified.[4,5,6] Several examples suggest that mobilization response is genetically determined: Humans subjected to successive cycles of G-CSF respondedPLOS ONE | DOI:10.1371/journal.pone.0121859 March 24, 2015SNP rs1801157 and Mobilization Efficiency. Three small studies on autologous donors or healthy volunteer donors suggested a correlation between a single-nucleotide polymorphism (SNP) in the 3’URT of CXCL12ß, rs1801157, and G-CSF mobilization efficiency, which promised to be a break-through discovery in this field.[9,10,11]
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