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Cancer-associated rs6983267 SNP and its accompanying long non-coding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations

ABSTRACT: Cancer-associated rs6983267 SNP and its accompanying long non-coding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations

PROVIDER: PRJNA417282 | ENA |

REPOSITORIES: ENA

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Cancer-associated rs6983267 SNP and its accompanying long non-coding RNA CCAT2 induce myeloid malignancies via unique SNP-specific RNA mutations

Project description:The cancer-risk associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long non-coding RNA CCAT2 in the highly amplified 8q24.21 region has been implicated in cancer predisposition, though causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 induces global deregulation of gene expression by downregulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel disease-specific RNA mutation (named DNA-to-RNA allelic imbalance, DRAI) at the SNP locus in MDS/MPN patients and CCAT2-transgenic mice. The RNA transcribed from the SNP locus in malignant hematopoietic cells have different allelic composition from the corresponding genomic DNA, a phenomenon rarely observed in normal cells. Our findings provide fundamental insights into the functional role of rs6983267 SNP and CCAT2 in myeloid malignancies. We performed genome-wide microarray expression profiling to study the genetic landscape alterations induced by CCAT2 and DRAI

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