title: PVT1 dependence in cancer with MYC copy-number increase.
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.
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Yuen-Yi
authors.initials: YY
authors.lastname: Tseng
authors.affiliation: 1] Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
authors.forename: Branden S
authors.initials: BS
authors.lastname: Moriarity
authors.affiliation: 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].
authors.forename: Wuming
authors.initials: W
authors.lastname: Gong
authors.affiliation: 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.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Akiyama
authors.affiliation: 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.
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Tiwari
authors.affiliation: 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.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kawakami
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ronning
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Reuland
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Kacey
authors.initials: K
authors.lastname: Guenther
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Beadnell
authors.affiliation: Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Essig
authors.affiliation: Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: George M
authors.initials: GM
authors.lastname: Otto
authors.affiliation: Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA.
authors.forename: M Gerard
authors.initials: MG
authors.lastname: O'Sullivan
authors.affiliation: 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.
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.affiliation: 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].
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Schwertfeger
authors.affiliation: 1] Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA [2].
authors.forename: York
authors.initials: Y
authors.lastname: Marahrens
authors.affiliation: 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].
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kawakami
authors.affiliation: 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.
authors.forename: Anindya
authors.initials: A
authors.lastname: Bagchi
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D056915:DNA Copy Number Variations / Q000235:genetics*; D004195:Disease Models, Animal; D005784:Gene Amplification / Q000235:genetics*; D018628:Gene Dosage / Q000235:genetics*; D016259:Genes, myc / Q000235:genetics*; D045325:HCT116 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D062085:RNA, Long Noncoding / Q000235:genetics*
chemical_list: D016274:Oncogene Protein p55(v-myc); C521123:PVT1 long-non-coding RNA, human; D062085:RNA, Long Noncoding