Cancer-associated rs6983267 SNP and its accompanying long noncoding RNACCAT2induce myeloid malignancies via unique SNP-specific RNA mutations
Year: 2018
Type: preprint
Abstract: The cancer-risk-associated rs6983267 single nucleotide polymorphism (SNP) and the accompanying long noncoding RNACCAT2in the highly amplified 8q24.21 region have been implicated in cancer predisposition, although causality has not been established. Here, using allele-specificCCAT2transgenic mice, we demonstrate thatCCAT2overexpression leads to spontaneous myeloid malignancies. We further identified thatCCAT2is overexpressed in bone marrow and peripheral blood of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients.CCAT2induces 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 andCCAT2-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 andCCAT2in myeloid malignancies.
Source: Genome Research
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
Institutions: The University of Texas MD Anderson Cancer Center, University of Bologna, Iuliu Hațieganu University of Medicine and Pharmacy, Universidade do Porto, i3S - Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Arcispedale Sant'Anna, Karolinska Institutet, Institute of Oncology Prof. Dr. Ion Chiricuta, Indiana University Indianapolis, Indiana University School of Medicine, University of Southern California, Children's Hospital Los Angeles, USC Norris Comprehensive Cancer Center, Saban Research Institute, Erasmus MC, Erasmus MC Cancer Institute
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: bronze
Funders: RGK Foundation, Cancer Prevention and Research Institute of Texas, Duncan Family Institute for Cancer Prevention and Risk Assessment, AIM at Melanoma, Laura and John Arnold Foundation, Stichting voor de Blinden, Cancerfonden, Karolinska Institutet, Vetenskapsrådet, Barncancerfonden, National Institutes of Health, University of Texas MD Anderson Cancer Center, National Cancer Institute, National Center for Advancing Translational Sciences, Moonshot Research and Development Program
Awards: SPORE University of Texas M. D. Anderson Cancer Center-Leukemia, G1943345356, G2284200960, G2947552126, G3015188539, Novel Targets for Acute Myeloid Leukemia Treatment, CHARACTERIZATION AND TARGETED THERAPY OF T-ALL DEFICIENT FOR PTEN AND INK4A/ARF, Novel extra cellular RNA-based combinatorial RNA inhibition therapy, G5974234380, G6526681941, Protein-coding and non-coding RNA biomarkers for early detection of CLL, Genetic Epidemiology of non-Hodgkin Lymphoma, G816327597, G8817362204, G9000100142, G9000209611, G9000223477, SPORE in Brain Cancer, The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
OpenAlex ID: W2958277374