Evidence that 6q25.1 variant rs6931104 confers susceptibility to chronic myeloid leukemia through RMND1 regulation

Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder. Our previous study reported novel loci as genetic markers associated with increased susceptibility to CML. The present study conducted an expression quantitative trait loci (eQTL) analysis to confirm that the single nucleotide polymorphisms (SNPs) at these loci affect the expression of candidate CML-susceptible genes. We identified that three SNPs (rs963193, rs6931104, and rs9371517) were related to the gene expression pattern of RMND1 (Required For Meiotic Nuclear Division 1 Homolog) in both granulocytes and mononuclear cells from 83 healthy donors. Furthermore, reduced expression of RMND1 expression was noted in CML patients compared with that in healthy individuals. We used the eQTL browsing tool to assess the regulatory information on the three associated significant SNPs, out of which rs6931104 showed strong evidence of regulatory effects. Chromatin immunoprecipitation (ChIP) assays demonstrated that A alleles of rs6931104 could significantly change the binding affinity of transcription factor (TF) RFX3 compared to the G alleles. Then, we performed in vitro experiments on BCR-ABL1-positive (BCR-ABL1(+)) cell lines. We found that expression of the CML-susceptible gene RMND1 is affected by the binding affinity of TF RFX3, suggesting that RFX3 plays a role in RMND1 expression. Our findings suggest potential target genes for associations of genetic susceptibility risk loci and provide further insights into the pathogenesis and mechanism of CML.