Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain

  1. Shuning He
  2. Marc R Mansour
  3. Mark W Zimmerman
  4. Dong Hyuk Ki
  5. Hillary M Layden
  6. Koshi Akahane
  7. Evisa Gjini
  8. Eric D de Groh
  9. Antonio R Perez-Atayde
  10. Shizhen Zhu
  11. Jonathan A Epstein
  12. A Thomas Look  Is a corresponding author
  1. Harvard Medical School, United States
  2. Perelman School of Medicine at the University of Pennsylvania, United States

Abstract

Earlier reports showed that hyperplasia of sympathoadrenal cell precursors during embryogenesis in Nf1-deficient mice is independent of Nf1's role in down-modulating RAS-MAPK signaling. We demonstrate in zebrafish that nf1 loss leads to aberrant activation of RAS signaling in MYCN-induced neuroblastomas that arise in these precursors, and that the GTPase-activating protein (GAP)-related domain (GRD) is sufficient to suppress the acceleration of neuroblastoma in nf1-deficient fish, but not the hypertrophy of sympathoadrenal cells in nf1 mutant embryos. Thus, even though neuroblastoma is a classical 'developmental tumor', NF1 relies on a very different mechanism to suppress malignant transformation than it does to modulate normal neural crest cell growth. We also show marked synergy in tumor cell killing between MEK inhibitors (trametinib) and retinoids (isotretinoin) in primary nf1a-/- zebrafish neuroblastomas. Thus, our model system has considerable translational potential for investigating new strategies to improve the treatment of very high-risk neuroblastomas with aberrant RAS-MAPK activation.

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Author details

  1. Shuning He

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Marc R Mansour

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Mark W Zimmerman

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Dong Hyuk Ki

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Hillary M Layden

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Koshi Akahane

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Evisa Gjini

    Center for Immuno-Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Eric D de Groh

    Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Antonio R Perez-Atayde

    Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Shizhen Zhu

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Jonathan A Epstein

    Department of Cell and Developmental Biology, Penn Cardiovascular Institute, and the Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. A Thomas Look

    Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, United States
    For correspondence
    thomas_look@dfci.harvard.edu
    Competing interests
    The authors declare that no competing interests exist.

Ethics

Animal experimentation: All zebrafish studies and maintenance of the animals were performed in accordance with Dana-Farber Cancer Institute IACUC-approved protocol (#02-107).

Reviewing Editor

  1. Richard J Gilbertson, Cambridge Cancer Center, CRUK Cambridge Institute, United Kingdom

Publication history

  1. Received: January 26, 2016
  2. Accepted: April 26, 2016
  3. Accepted Manuscript published: April 27, 2016 (version 1)
  4. Version of Record published: June 9, 2016 (version 2)

Copyright

© 2016, He et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Shuning He
  2. Marc R Mansour
  3. Mark W Zimmerman
  4. Dong Hyuk Ki
  5. Hillary M Layden
  6. Koshi Akahane
  7. Evisa Gjini
  8. Eric D de Groh
  9. Antonio R Perez-Atayde
  10. Shizhen Zhu
  11. Jonathan A Epstein
  12. A Thomas Look
(2016)
Synergy between loss of NF1 and overexpression of MYCN in neuroblastoma is mediated by the GAP-related domain
eLife 5:e14713.
https://doi.org/10.7554/eLife.14713

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