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Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma

Kerosuo, Laura and Neppala, Pushpa and Hsin, Jenny and Mohlin, Sofie and Vieceli, Felipe Monteleone and Török, Zsofia and Laine, Anni and Westermarck, Jukka and Bronner, Marianne E. (2018) Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma. Proceedings of the National Academy of Sciences of the United States of America, 115 (31). E7351-E7360. ISSN 0027-8424. PMCID PMC6077707. http://resolver.caltech.edu/CaltechAUTHORS:20180718-144644668

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Abstract

Neuroblastoma is a neural crest-derived childhood tumor of the peripheral nervous system in which MycN amplification is a hallmark of poor prognosis. Here we show that MycN is expressed together with phosphorylation-stabilizing factor CIP2A in regions of the neural plate destined to form the CNS, but MycN is excluded from the neighboring neural crest stem cell domain. Interestingly, ectopic expression of MycN or CIP2A in the neural crest domain biases cells toward CNS-like neural stem cells that express Sox2. Consistent with this, some forms of neuroblastoma have been shown to share transcriptional resemblance with CNS neural stem cells. As high MycN/CIP2A levels correlate with poor prognosis, we posit that a MycN/CIP2A-mediated cell-fate bias may reflect a possible mechanism underlying early priming of some aggressive forms of neuroblastoma. In contrast to MycN, its paralogue cMyc is normally expressed in the neural crest stem cell domain and typically is associated with better overall survival in clinical neuroblastoma, perhaps reflecting a more “normal” neural crest-like state. These data suggest that priming for some forms of aggressive neuroblastoma may occur before neural crest emigration from the CNS and well before sympathoadrenal specification.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1073/pnas.1800039115DOIArticle
http://www.pnas.org/lookup/suppl/doi:10.1073/pnas.1800039115/-/DCSupplementalPublisherSupporting Information
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6077707/PubMed CentralArticle
ORCID:
AuthorORCID
Kerosuo, Laura0000-0001-6710-3512
Mohlin, Sofie0000-0002-2458-3963
Vieceli, Felipe Monteleone0000-0001-5142-8224
Bronner, Marianne E.0000-0003-4274-1862
Additional Information:© 2018 The Author(s). Published under the PNAS license. Contributed by Marianne E. Bronner, June 13, 2018 (sent for review January 3, 2018; reviewed by Angela Nieto and Carol Thiele-Galetto) ; published ahead of print July 18, 2018. https://doi.org/10.1073/pnas.1800039115 We thank Dr. Marie Arsenian-Henriksson for providing SK-N-BE(2) cells, Dr. Kristina Cole for providing NGP cells, Dr. Ruth Palmer for providing SK-N-AS cells, and Dr. Edward K. Chan for the mouse monoclonal CIP2A antibody. This work was funded by NIH Grants HD037105 and DE024157 (to M.E.B.) and by grants from the Jane and Aatos Erkko Foundation, the Ella and Georg Ehrnrooth Foundation, and the Väre Foundation (to L.K.), the American-Scandinavian Foundation (to P.N.), and the Sigrid Juselius Foundation (to J.W.). Author contributions: L.K., P.N., S.M., J.W., and M.E.B. designed research; L.K., P.N., J.H., F.M.V., Z.T., and A.L. performed research; L.K. and S.M. contributed new reagents/analytic tools; L.K., P.N., J.H., S.M., and F.M.V. analyzed data; and L.K., S.M., J.W., and M.E.B. wrote the paper. Reviewers: A.N., Instituto de Neurociencias de Alicante, Consejo Superior de Investigaciones Científicas-Universidad Miguel Hernández; and C.T.-G., National Institutes of Health. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1800039115/-/DCSupplemental.
Funders:
Funding AgencyGrant Number
NIHHD037105
NIHDE024157
Jane and Aatos Erkko FoundationUNSPECIFIED
Ella and Georg Ehrnrooth FoundationUNSPECIFIED
Väre FoundationUNSPECIFIED
American-Scandinavian FoundationUNSPECIFIED
Sigrid Juselius FoundationUNSPECIFIED
Subject Keywords:neuroblastoma initiation | MycN | CIP2A | neural crest | Sox2
PubMed Central ID:PMC6077707
Record Number:CaltechAUTHORS:20180718-144644668
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20180718-144644668
Official Citation:Enhanced expression of MycN/CIP2A drives neural crest toward a neural stem cell-like fate: Implications for priming of neuroblastoma Laura Kerosuo, Pushpa Neppala, Jenny Hsin, Sofie Mohlin, Felipe Monteleone Vieceli, Zsofia Török, Anni Laine, Jukka Westermarck, Marianne E. Bronner Proceedings of the National Academy of Sciences Jul 2018, 115 (31) E7351-E7360; DOI: 10.1073/pnas.1800039115
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:87968
Collection:CaltechAUTHORS
Deposited By: George Porter
Deposited On:18 Jul 2018 21:55
Last Modified:25 Mar 2019 18:28

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