Vol 7: Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.Reportar como inadecuado



 Vol 7: Polymorphisms in microRNA target sites modulate risk of lymphoblastic and myeloid leukemias and affect microRNA binding.


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This article is from Journal of Hematology & Oncology, volume 7.AbstractBackground: 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.



Autor: Dzikiewicz-Krawczyk, Agnieszka; Macieja, Anna; Maly, Ewa; Januszkiewicz-Lewandowska, Danuta; Mosor, Maria; Fichna, Marta; Strauss, Ewa; Nowak, Jerzy

Fuente: https://archive.org/







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