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

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.

SUBMITTER: Woo YM

PROVIDER: S-EPMC6592567 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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

Woo Young Min YM Kim Sehwa S Park Jong-Ho JH Lee Nan Young NY Kim Jong-Won JW Kim Dennis Dong Hwan DDH

PloS one 20190625 6

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 patte ...[more]

PMID: 31237926

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Project description:The first treatment of chronic myeloid leukemia (CML) included spleen x-radiation and conventional drugs, mainly Busulfan and Hydroxyurea. This therapy improved the quality of life during the chronic phase of the disease, without preventing nor significantly delaying the progression towards advanced phases. The introduction of allogeneic stem cell transplantation (alloSCT) marked the first important breakthrough in the evolution of CML treatment, because about 50% of the eligible patients were cured. The second breakthrough was the introduction of human recombinant interferon-alfa, able to achieve a complete cytogenetic remission in 15% to 30% of patients, with a significant survival advantage over conventional chemotherapy. At the end of the last century, about 15 years ago, all these treatments were quickly replaced by a class of small molecules targeting the tyrosine kinases (TK), which were able to induce a major molecular remission in most of the patients, without remarkable side effects, and a very prolonged life-span. The first approved TK inhibitor (TKI) was Imatinib Mesylate (Glivec or Gleevec, Novartis). Rapidly, other TKIs were developed tested and commercialized, namely Dasatinib (Sprycel, Bristol-Myers Squibb), Nilotinib (Tasigna, Novartis), Bosutinib (Busulif, Pfizer) and Ponatinib (Iclusig, Ariad). Not all these compounds are available worldwide; some of them are approved only for second line treatment, and the high prices are a problem that can limit their use. A frequent update of treatment recommendations is necessary. The current treatment goals include not only the prevention of the transformation to the advanced phases and the prolongation of survival, but also a length of survival and of a quality of life comparable to that of non-leukemic individuals. In some patient the next ambitious step is to move towards a treatment-free remission. The CML therapy, the role of alloSCT and the promising experimental strategies are reviewed in the context of the new therapeutic goals.

Dataset Information

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

Publications

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

Similar Datasets

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