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

  1. George A. Calin1,4
  1. 1Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  2. 2Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40126 Bologna, Italy;
  3. 3The Research Center for Functional Genomics, Biomedicine and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 400012 Cluj Napoca, Romania;
  4. 4Center for RNA Interference and Non-coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  5. 5Institute for Research and Innovation in Health (I3S), and Institute of Biomedical Engineering (INEB), University of Porto, 4200-135, Porto, Portugal;
  6. 6Hematology Section, Azienda Ospedaliero-Universitaria Arcispedale S. Anna, 44124, Ferrara, Italy;
  7. 7Department of Oncology-Pathology, Karolinska Institute, Cancer Center Karolinska, SE-171 77 Stockholm, Sweden;
  8. 8Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  9. 9Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  10. 10Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  11. 11Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  12. 12Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  13. 13Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  14. 14Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  15. 15Department of Hematology, The Oncology Institute Ion Chiricuta, 400015 Cluj Napoca, Romania;
  16. 16Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA;
  17. 17Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA;
  18. 18Departments of Pediatrics and Molecular Microbiology and Immunology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Children's Center for Cancer and Blood Diseases and The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, California 90027, USA;
  19. 19Department of Pathology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 CE Rotterdam, The Netherlands;
  20. 20Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA

  • ↵Present addresses: 21ProQR Therapeutics N.V., 2333 CK Leiden, The Netherlands; 22Medical and Molecular Genetics Department, Indiana University, Indianapolis, IN 46202, USA; 23Cell & Gene Therapy, Bioverativ Inc., Waltham, MA 02451

  • Corresponding author: gcalin{at}mdanderson.org

    • 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.

    Footnotes

    • Received May 16, 2017.
    • Accepted February 28, 2018.

    This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.

    This Article

    1. Published in Advance March 22, 2018, doi: 10.1101/gr.225128.117 Genome Res. © 2018 Shah et al.; Published by Cold Spring Harbor Laboratory Press

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