Abstract

Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.

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Acknowledgements

G.Q.D. is supported by National Institutes of Health grant R01GM107536, Alex’s Lemonade Stand Foundation, and the Ellison Medical Foundation. G.Q.D. is an affiliate member of the Broad Institute, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research. J.T.P. was supported by Alex’s Lemonade Stand Foundation. K.M.T. was supported as a Howard Hughes Medical Institute International Student Research Fellow and as a Herchel Smith Graduate Fellow. D.S.P. and R.E. were supported by award number T32GM007753 from the National Institute of General Medical Sciences.

Author information

Affiliations

  1. Division of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • John T. Powers
    • , Kaloyan M. Tsanov
    • , Daniel S. Pearson
    • , Richard Ebright
    • , Marc Seligson
    • , Yvanka de Soysa
    • , Patrick Cahan
    • , Ho-Chou Tu
    • , Areum Han
    • , Grace S. LaPier
    • , Jihan K. Osborne
    • , Samantha J. Ross
    • , Marcella Cesana
    •  & George Q. Daley
  2. Department of Pediatric Oncology, University Hospital Köln, Köln 50937, Germany

    • Frederik Roels
    • , Jessica Theißen
    •  & Frank Berthold
  3. Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, USA

    • Catherine S. Spina
    •  & James J. Collins
  4. Department of Pathology, Boston Children’s Hospital, Boston Massachusetts 02215, USA

    • Kyle C. Kurek
  5. Department of Biological Engineering, Massachusetts Institute of Technology, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA

    • James J. Collins
  6. Stem Cell Transplantation Program, Dana Farber Cancer Institute & Boston Children’s Hospital, Boston, Massachusetts 02115, USA

    • George Q. Daley
  7. Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • George Q. Daley
  8. Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA

    • George Q. Daley

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Contributions

G.Q.D. provided support and guidance for this work; G.Q.D. and J.T.P. conceived the hypothesis, designed the study, and wrote the manuscript; J.T.P. performed and interpreted most of the experiments and generated figures; K.M.T. helped perform the shRNA and siRNA experiments and generated most of the plasmid constructs; D.S.P. helped perform the RNA sequencing experiments; F.R., J.T., and F.B. generated the aCGH and survival data on neuroblastoma patients; C.S.S., K.C.K., and J.J.C. acquired tissue samples and assisted with the IHC analysis; R.E. assisted with the CRISPR experiments; M.S., Y.d.S., G.S.LP., and S.J.R. provided technical help; P.C. processed RNA sequencing data and helped with data analysis; H.C.T. helped perform in vitro transfection experiments; A.H. assisted with RNA sequencing data analysis; J.K.O. and C.S.S. performed xenograft experiments; M.C. assisted with the RNA sequencing experiments.

Competing interests

G.Q.D. holds options and intellectual property relating to 28/7 Therapeutics, a company seeking to develop inhibitors of the LIN28/let-7 pathway.

Corresponding author

Correspondence to George Q. Daley.

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    Supplementary Information

    This file contains Supplementary Figure 1 (western blot scans) and Supplementary Figure 2 (Xenograft tumor images).

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https://doi.org/10.1038/nature18632

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