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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Journal of Hematology & Oncology 1/2014

Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding

Zeitschrift:
Journal of Hematology & Oncology > Ausgabe 1/2014
Autoren:
Agnieszka Dzikiewicz-Krawczyk, Anna Macieja, Ewa Mały, Danuta Januszkiewicz-Lewandowska, Maria Mosor, Marta Fichna, Ewa Strauss, Jerzy Nowak
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1756-8722-7-43) contains supplementary material, which is available to authorized users.

Competing interests

The authors report no conflicts of interest.

Authors’ contributions

ADK conceived the study, performed the experiments, analyzed the data, interpreted the results and wrote the manuscript. AM participated in the laboratory work. EM, MM and DJL recruited the patients. MF and ES recruited the control group. JN participated in the design of the study; DJL, MM and JN critically reviewed the manuscript. All authors read and approved the final manuscript.

Abstract

Background

MicroRNA dysregulation is a common event in leukemia. Polymorphisms in microRNA-binding sites (miRSNPs) in target genes may alter the strength of microRNA interaction with target transcripts thereby affecting protein levels. In this study we aimed at identifying miRSNPs associated with leukemia risk and assessing impact of these miRSNPs on miRNA binding to target transcripts.

Methods

We analyzed with specialized algorithms the 3′ untranslated regions of 137 leukemia-associated genes and identified 111 putative miRSNPs, of which 10 were chosen for further investigation. We genotyped patients with acute myeloid leukemia (AML, n = 87), chronic myeloid leukemia (CML, n = 140), childhood acute lymphoblastic leukemia (ALL, n = 101) and healthy controls (n = 471). Association between SNPs and leukemia risk was calculated by estimating odds ratios in the multivariate logistic regression analysis. For miRSNPs that were associated with leukemia risk we performed luciferase reporter assays to examine whether they influence miRNA binding.

Results

Here we show that variant alleles of TLX1 _rs2742038 and ETV6 _rs1573613 were associated with increased risk of childhood ALL (OR (95% CI) = 3.97 (1.43-11.02) and 1.9 (1.16-3.11), respectively), while PML _rs9479 was associated with decreased ALL risk (OR = 0.55 (0.36-0.86). In adult myeloid leukemias we found significant associations between the variant allele of PML _rs9479 and decreased AML risk (OR = 0.61 (0.38-0.97), and between variant alleles of IRF8 _ rs10514611 and ARHGAP26 _rs187729 and increased CML risk (OR = 2.4 (1.12-5.15) and 1.63 (1.07-2.47), respectively). Moreover, we observed a significant trend for an increasing ALL and CML risk with the growing number of risk genotypes with OR = 13.91 (4.38-44.11) for carriers of ≥3 risk genotypes in ALL and OR = 4.9 (1.27-18.85) for carriers of 2 risk genotypes in CML. Luciferase reporter assays revealed that the C allele of ARHGAP26 _rs187729 creates an illegitimate binding site for miR-18a-3p, while the A allele of PML _rs9479 enhances binding of miR-510-5p and the C allele of ETV6 _rs1573613 weakens binding of miR-34c-5p and miR-449b-5p.

Conclusions

Our study implicates that microRNA-binding site polymorphisms modulate leukemia risk by interfering with the miRNA-mediated regulation. Our findings underscore the significance of variability in 3′ untranslated regions in leukemia.

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Zusatzmaterial
Authors’ original file for figure 1
13045_2014_401_MOESM1_ESM.tif
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