Cancer-associated rs6983267 SNP and its accompanying long noncoding RNA<i>CCAT2</i>induce myeloid malignancies via unique SNP-specific RNA mutations

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA <i>CCAT2</i> in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific <i>CCAT2</i> transgenic mice, we demonstrate that <i>CCAT2</i> overexpression leads to spontaneous myeloid malignancies. We further identified that <i>CCAT2</i> is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. <i>CCAT2</i> induces global deregulation of gene expression by down-regulating EZH2 in vitro and in vivo in an allele-specific manner. We also identified a novel non-APOBEC, non-ADAR, RNA editing at the SNP locus in MDS/MPN patients and <i>CCAT2</i>-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 <i>CCAT2</i> in myeloid malignancies.