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Abstract

‘Gain’ of supernumerary copies of the 8q24.21 chromosomal region has been shown to be common in many human cancers1,2,3,4,5,6,7,8,9,10,11,12,13 and is associated with poor prognosis7,10,14. 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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Change history

  • 06 August 2014

    Figure 2a, b, d scale bars were missing and have been added. Minor edits were made to the Fig. 2 legend.

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Acknowledgements

We thank A. T. Vogel for writing statistical analysis scripts; Research Animal Resources, University of Minnesota, for maintaining the mouse colony; S. Horn and L. Oseth for embryonic stem cell blastocyst injection and FISH analysis respectively. This work was supported by Masonic Cancer Center Laboratory start-up funds (to A.B.), and by grants from the Masonic Scholar Award (to A.B.), the Karen Wyckoff Rein in Sarcoma Fund (to A.B.), Translational Workgroup Pilot Project Awards by the Institute of Prostate and Urologic Cancer, University of Minnesota (to A.B.) and an American Cancer Society Institutional Research Grant (award 118198-IRG-58-001-52-IRG92, to A.B.). A.T. was supported by an Indo-US fellowship from the Indo-US Science and Technology Forum.

Author information

Author notes

    • Branden S. Moriarity
    • , Wuming Gong
    • , Kathryn L. Schwertfeger
    • , York Marahrens
    •  & Yasuhiko Kawakami

    These authors contributed equally to this work.

    • Ashutosh Tiwari

    Present address: Center for Bio-Design, Translational Health Science and Technology Institute, Gurgaon 122016, India.

Affiliations

  1. Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA

    • Yuen-Yi Tseng
    • , Wuming Gong
    • , Ryutaro Akiyama
    • , Hiroko Kawakami
    • , Peter Ronning
    • , Brian Reuland
    • , Kacey Guenther
    • , Jaclyn Essig
    • , David A. Largaespada
    • , York Marahrens
    • , Yasuhiko Kawakami
    •  & Anindya Bagchi
  2. Masonic Cancer Center, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA

    • Branden S. Moriarity
    • , Wuming Gong
    • , Ashutosh Tiwari
    • , George M. Otto
    • , M. Gerard O’Sullivan
    • , David A. Largaespada
    • , Kathryn L. Schwertfeger
    •  & Anindya Bagchi
  3. Stem Cell Institute, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA

    • Ryutaro Akiyama
    • , Hiroko Kawakami
    •  & Yasuhiko Kawakami
  4. Department of Laboratory Medicine and Pathology, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA

    • Thomas C. Beadnell
    •  & Kathryn L. Schwertfeger

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Contributions

Y.Y.T. and A.B. conceptualized the research programme and designed the experiments; Y.Y.T., B.S.M., H.K., A.T., R.A., P.R., B.R., K.G., T.C.B., J.E., Y.K. and A.B. performed the experiments. Y.Y.T. and W.G. analysed the data; M.G.O. and Y.Y.T. performed the histological analyses; K.L.S., D.A.L., Y.M., Y.K. and A.B. supervised experiments and data analysis; A.B. and Y.M. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Anindya Bagchi.

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DOI

https://doi.org/10.1038/nature13311

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