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

Abstract

The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNA CCAT2 in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specific CCAT2 transgenic mice, we demonstrate that CCAT2 overexpression leads to spontaneous myeloid malignancies. We further identified that CCAT2 is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. CCAT2 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 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.

• Authors: Maitri Y Shah, Manuela Ferracin, Valentina Pileczki, Baoqing Chen, Roxana Redis, Linda Fabris, Xinna Zhang, Cristina Ivan, Masayoshi Shimizu, Cristian Rodriguez-Aguayo, Mihnea Dragomir, Katrien Van Roosbroeck, Maria Ines Almeida, Maria Ciccone, Daniela Nedelcu, Maria Angelica Cortez, Taghi Manshouri, Steliana Calin, Muharrem Muftuoglu, Pinaki P Banerjee, Mustafa H Badiwi, Jan Parker-Thornburg, Asha Multani, James William Welsh, Marcos Roberto Estecio, Hui Ling, Ciprian Tomuleasa, Delia Dima, Hui Yang, Hector Alvarez, M James You, Milan Radovich, Elizabeth Shpall, Muller Fabbri, Katy Rezvani, Leonard Girnita, Ioana Berindan-Neagoe, Anirban Maitra, Srdan Verstovsek, Riccardo Fodde, Carlos Bueso-Ramos, Mihai Gagea, Guillermo Garcia Manero, George A Calin
• Journal: Genome research (Genome Res) Vol. 28 Issue 4 Pg. 432-447 (04 2018) ISSN: 1549-5469 [Electronic] United States
• PMID: 29567676 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 Shah et al.; Published by Cold Spring Harbor Laboratory Press.

Chemical References

• RNA, Long Noncoding
• long non-coding RNA CCAT2, human

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Cell Line, Tumor
• Cell Proliferation (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice
• Mice, Transgenic
• Middle Aged
• Myelodysplastic-Myeloproliferative Diseases (genetics, pathology)
• Polymorphism, Single Nucleotide (genetics)
• RNA Editing (genetics)
• RNA, Long Noncoding (genetics)