PVT1 dependence in cancer with MYC copy-number increase

Yuen Yi Tseng, Branden S. Moriarity, Wuming Gong, Ryutaro Akiyama, Ashutosh Tiwari, Hiroko Kawakami, Peter Ronning, Brian Reuland, Kacey Guenther, Thomas C. Beadnell, Jaclyn Essig, George M. Otto, M. Gerard O'Sullivan, David A. Largaespada, Kathryn L. Schwertfeger, York Marahrens, Yasuhiko Kawakami, Anindya Bagchi

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)82-86
Number of pages5
JournalNature
Volume512
Issue number1
DOIs
StatePublished - Jan 1 2014

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Long Noncoding RNA
Neoplasms
Genes
Proteins
myc Genes
Oncogenes
Colonic Neoplasms
Chromosomes
RNA
Therapeutics

Cite this

Tseng, Y. Y., Moriarity, B. S., Gong, W., Akiyama, R., Tiwari, A., Kawakami, H., ... Bagchi, A. (2014). PVT1 dependence in cancer with MYC copy-number increase. Nature, 512(1), 82-86. https://doi.org/10.1038/nature13311

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.

In: Nature, Vol. 512, No. 1, 01.01.2014, p. 82-86.

Research output: Contribution to journalArticle

Tseng, YY, Moriarity, BS, Gong, W, Akiyama, R, Tiwari, A, Kawakami, H, Ronning, P, Reuland, B, Guenther, K, Beadnell, TC, Essig, J, Otto, GM, O'Sullivan, MG, Largaespada, DA, Schwertfeger, KL, Marahrens, Y, Kawakami, Y & Bagchi, A 2014, 'PVT1 dependence in cancer with MYC copy-number increase', Nature, vol. 512, no. 1, pp. 82-86. https://doi.org/10.1038/nature13311
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. / PVT1 dependence in cancer with MYC copy-number increase. In: Nature. 2014 ; Vol. 512, No. 1. pp. 82-86.
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AU - O'Sullivan, M. Gerard

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