Abstract
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.
Highlights
We examined the associations of 41 single nucleotide polymorphisms (SNPs) at two loci, 6q25.1 and 17p11.1 (Table 1), in 83 healthy individuals to evaluate whether those SNPs were functional
We focused on nine genes that had previously been reported [5] in the regions of 6q25.1 (MTHFD1L, AKAP12, ZBTB2, RMND1, C6orf211, C6orf97, ESR1) and 17p11.1 (FAM27L, WSB1)
According to the results of the genotype-tissue expression (GTEx) project, nearly 50% of the genetic variants associated with human disease colocalize with an expression quantitative trait loci (eQTL) [19]
Summary
Chronic myeloid leukemia (CML) is a clonal disorder in hematopoietic stem cells characterized by the presence of an oncogenic BCR-ABL1 fusion gene that encodes a constitutively. Evidence that SNP rs6931104 confers susceptibility to chronic myeloid leukemia through RMND1 regulation activated fusion protein carrying tyrosine kinase activity. Genome-wide association studies (GWASs) have revealed that single nucleotide polymorphisms (SNPs) are associated with CML development, progression, and treatment outcome [1,2,3,4]. We performed a genome-wide analysis and reported novel loci associated with susceptibility to CML. To understand the functional role of these SNPs, we conducted expression quantitative trait loci (eQTL) and functional analysis of related transcription factor in confirming whether the SNPs in these loci affect the expression of CML susceptibility candidate genes
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