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PVT1 dependence in cancer with MYC copy-number increase.
Tseng, Yuen-Yi; Moriarity, Branden S; Gong, Wuming; Akiyama, Ryutaro; Tiwari, Ashutosh; Kawakami, Hiroko; Ronning, Peter; Reuland, Brian; Guenther, Kacey; Beadnell, Thomas C; Essig, Jaclyn; Otto, George M; O'Sullivan, M Gerard; Largaespada, David A; Schwertfeger, Kathryn L; Marahrens, York; Kawakami, Yasuhiko; Bagchi, Anindya.
Affiliation
  • Tseng YY; Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Moriarity BS; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
  • Gong W; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
  • Akiyama R; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Tiwari A; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India.
  • Kawakami H; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Ronning P; Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Reuland B; Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Guenther K; Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Beadnell TC; Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Essig J; Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Otto GM; Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • O'Sullivan MG; Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Largaespada DA; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
  • Schwertfeger KL; 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
  • Marahrens Y; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
  • Kawakami Y; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [3].
  • Bagchi A; 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
Nature ; 512(7512): 82-6, 2014 Aug 07.
Article in En | MEDLINE | ID: mdl-25043044
ABSTRACT
'Gain' of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers and is associated with poor prognosis. The well-characterized myelocytomatosis (MYC) oncogene resides in the 8q24.21 region and is consistently co-gained with an adjacent 'gene desert' of approximately 2 megabases that contains the long non-coding RNA gene PVT1, the CCDC26 gene candidate and the GSDMC gene. Whether low copy-number gain of one or more of these genes drives neoplasia is not known. Here we use chromosome engineering in mice to show that a single extra copy of either the Myc gene or the region encompassing Pvt1, Ccdc26 and Gsdmc fails to advance cancer measurably, whereas a single supernumerary segment encompassing all four genes successfully promotes cancer. Gain of PVT1 long non-coding RNA expression was required for high MYC protein levels in 8q24-amplified human cancer cells. PVT1 RNA and MYC protein expression correlated in primary human tumours, and copy number of PVT1 was co-increased in more than 98% of MYC-copy-increase cancers. Ablation of PVT1 from MYC-driven colon cancer line HCT116 diminished its tumorigenic potency. As MYC protein has been refractory to small-molecule inhibition, the dependence of high MYC protein levels on PVT1 long non-coding RNA provides a much needed therapeutic target.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Amplification / Genes, myc / Oncogene Protein p55(v-myc) / Gene Dosage / DNA Copy Number Variations / RNA, Long Noncoding Limits: Animals / Humans Language: En Journal: Nature Year: 2014 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Gene Amplification / Genes, myc / Oncogene Protein p55(v-myc) / Gene Dosage / DNA Copy Number Variations / RNA, Long Noncoding Limits: Animals / Humans Language: En Journal: Nature Year: 2014 Type: Article Affiliation country: United States