This article has been updated


‘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.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

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.


  1. 1.

    , , & The 8q24 gene desert: an oasis of non-coding transcriptional activity. Front. Genet. 3, 69 (2012)

  2. 2.

    , , , & High-resolution analysis of copy number alterations and associated expression changes in ovarian tumors. BMC Med. Genomics 2, 21 (2009)

  3. 3.

    et al. Amplification of PVT1 contributes to the pathophysiology of ovarian and breast cancer. Clin. Cancer Res. 13, 5745–5755 (2007)

  4. 4.

    et al. High-resolution array comparative genomic hybridization of chromosome 8q: evaluation of putative progression markers for gastroesophageal junction adenocarcinomas. Cytogenet. Genome Res. 118, 130–137 (2007)

  5. 5.

    , , , & c-myc amplification is an independent prognostic factor in postmenopausal breast cancer. Int. J. Cancer 51, 687–691 (1992)

  6. 6.

    et al. Combined microarray analysis of small cell lung cancer reveals altered apoptotic balance and distinct expression signatures of MYC family gene amplification. Oncogene 25, 130–138 (2006)

  7. 7.

    et al. Clinical significance of alterations of chromosome 8 in high-grade, advanced, nonmetastatic prostate carcinoma. J. Natl Cancer Inst. 91, 1574–1580 (1999)

  8. 8.

    et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 67, 8504–8510 (2007)

  9. 9.

    et al. Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas. Cancer Res. 64, 4817–4825 (2004)

  10. 10.

    et al. Low-level copy number changes of MYC genes have a prognostic impact in medulloblastoma. J. Neurooncol. 102, 25–33 (2011)

  11. 11.

    et al. Frequent chromosome 8q gains in human small cell lung carcinoma detected by arbitrarily primed-PCR genomic fingerprinting. Cancer Genet. Cytogenet. 120, 11–17 (2000)

  12. 12.

    , , & Recurring chromosomal abnormalities in leukemia in PML-RARA transgenic mice parallel human acute promyelocytic leukemia. Blood 99, 2985–2991 (2002)

  13. 13.

    et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006)

  14. 14.

    et al. Quantitative analysis of chromosomal CGH in human breast tumors associates copy number abnormalities with p53 status and patient survival. Proc. Natl Acad. Sci. USA 98, 7952–7957 (2001)

  15. 15.

    , & Chromosome engineering in mice. Nature 378, 720–724 (1995)

  16. 16.

    et al. Prognostic relevance of gene amplifications and coamplifications in breast cancer. Cancer Res. 64, 8534–8540 (2004)

  17. 17.

    , , , & c-myc amplification is associated with HER2 amplification and closely linked with cell proliferation in tissue microarray of nonselected breast cancers. Hum. Pathol. 36, 634–639 (2005)

  18. 18.

    et al. Expression of the neu protooncogene in the mammary epithelium of transgenic mice induces metastatic disease. Proc. Natl Acad. Sci. USA 89, 10578–10582 (1992)

  19. 19.

    et al. Estrogen receptors α and β in the rodent mammary gland. Proc. Natl Acad. Sci. USA 97, 337–342 (2000)

  20. 20.

    et al. The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. J. Cell. Physiol. 213, 511–518 (2007)

  21. 21.

    et al. RNA-Seq of human neurons derived from iPS cells reveals candidate long non-coding RNAs involved in neurogenesis and neuropsychiatric disorders. PLoS ONE 6, e23356 (2011)

  22. 22.

    et al. Mechanistic insight into Myc stabilization in breast cancer involving aberrant Axin1 expression. Proc. Natl Acad. Sci. USA 109, 2790–2795 (2012)

  23. 23.

    et al. A signalling pathway controlling c-Myc degradation that impacts oncogenic transformation of human cells. Nature Cell Biol. 6, 308–318 (2004)

  24. 24.

    et al. Phosphorylation regulates c-Myc’s oncogenic activity in the mammary gland. Cancer Res. 71, 925–936 (2011)

  25. 25.

    et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997)

  26. 26.

    et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146, 904–917 (2011)

  27. 27.

    Transcription factors as targets for cancer therapy. Nature Rev. Cancer 2, 740–749 (2002)

  28. 28.

    & X-ray structures of Myc-Max and Mad-Max recognizing DNA. Molecular bases of regulation by proto-oncogenic transcription factors. Cell 112, 193–205 (2003)

  29. 29.

    et al. CHD5 is a tumor suppressor at human 1p36. Cell 128, 459–475 (2007)

  30. 30.

    et al. A critical role for the inflammatory response in a mouse model of preneoplastic progression. Cancer Res. 66, 5676–5685 (2006)

  31. 31.

    et al. Fibroblast growth factor receptor 1 activation in mammary tumor cells promotes macrophage recruitment in a CX3CL1-dependent manner. PLoS ONE 7, e45877 (2012)

  32. 32.

    , , & Three-dimensional culture models of normal and malignant breast epithelial cells. Nature Methods 4, 359–365 (2007)

  33. 33.

    et al. The morphologies of breast cancer cell lines in three-dimensional assays correlate with their profiles of gene expression. Mol. Oncol. 1, 84–96 (2007)

  34. 34.

    et al. Migration of cardiomyocytes is essential for heart regeneration in zebrafish. Development 139, 4133–4142 (2012)

  35. 35.

    , & RIP-Chip: the isolation and identification of mRNAs, microRNAs and protein components of ribonucleoprotein complexes from cell extracts. Nature Protocols 1, 302–307 (2006)

  36. 36.

    et al. Simple and efficient methods for enrichment and isolation of endonuclease modified cells. PloS One 9, e96114 (2014)

  37. 37.

    et al. Forward genetic screen for malignant peripheral nerve sheath tumor formation identifies new genes and pathways driving tumorigenesis. Nature Genet. 45, 756–766 (2013)

Download references


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.


  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


  1. Search for Yuen-Yi Tseng in:

  2. Search for Branden S. Moriarity in:

  3. Search for Wuming Gong in:

  4. Search for Ryutaro Akiyama in:

  5. Search for Ashutosh Tiwari in:

  6. Search for Hiroko Kawakami in:

  7. Search for Peter Ronning in:

  8. Search for Brian Reuland in:

  9. Search for Kacey Guenther in:

  10. Search for Thomas C. Beadnell in:

  11. Search for Jaclyn Essig in:

  12. Search for George M. Otto in:

  13. Search for M. Gerard O’Sullivan in:

  14. Search for David A. Largaespada in:

  15. Search for Kathryn L. Schwertfeger in:

  16. Search for York Marahrens in:

  17. Search for Yasuhiko Kawakami in:

  18. Search for Anindya Bagchi in:


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.

Extended data

About this article

Publication history





Further reading


By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.