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

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.

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Shah MY, Ferracin M, Pileczki V, Chen B, Redis R, Fabris L, Zhang X, Ivan C, Shimizu M, Rodriguez-Aguayo C, Dragomir M, Van Roosbroeck K, Almeida MI, Ciccone M, Nedelcu D, Cortez MA, Manshouri T, Calin S, Muftuoglu M, Banerjee PP, Badiwi MH, Parker-Thornburg J, Multani A, Welsh JW, Estecio MR, Ling H, Tomuleasa C, Dima D, Yang H, Alvarez H, You MJ, Radovich M, Shpall E, Fabbri M, Rezvani K, Girnita L, Berindan-Neagoe I, Maitra A, Verstovsek S, Fodde R, Bueso-Ramos C, Gagea M, Manero GG, Calin GA