Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

  1. Maja Solman
  2. Sasja Blokzijl-Franke
  3. Florian Piques
  4. Chuan Yan
  5. Qiqi Yang
  6. Marion Strullu
  7. Sarah M Kamel
  8. Pakize Ak
  9. Jeroen Bakkers
  10. David M Langenau
  11. Helene Cave
  12. Jeroen den Hertog  Is a corresponding author
  1. Hubrecht Institute-KNAW, Netherlands
  2. Hôpital Robert Debré, France
  3. Massachusetts General Hospital, United States
  4. University Medical Center Utrecht, Netherlands

Abstract

Gain-of-function mutations in the protein-tyrosine phosphatase SHP2 are the most frequently occurring mutations in sporadic juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) associated with Noonan syndrome (NS). Hematopoietic stem and progenitor cells (HSPCs) are the disease propagating cells of JMML. Here, we explored transcriptomes of HSPCs with Shp2 mutations derived from JMML patients and a novel NS zebrafish model. In addition to major NS traits, CRISPR/Cas9 knock-in Shp2D61G mutant zebrafish recapitulated a JMML-like MPN phenotype, including myeloid lineage hyperproliferation, ex vivo growth of myeloid colonies and in vivo transplantability of HSPCs. Single cell mRNA sequencing of HSPCs from Shp2D61G zebrafish embryos and bulk sequencing of HSPCs from JMML patients revealed an overlapping inflammatory gene expression pattern. Strikingly, an anti-inflammatory agent rescued JMML-like MPN in Shp2D61G zebrafish embryos. Our results indicate that a common inflammatory response was triggered in the HSPCs from sporadic JMML patients and syndromic NS zebrafish, which potentiated MPN and may represent a future target for JMML therapies.

Data availability

Sequencing data has been deposited to GEO under accession codes GSE167787 and GSE183252Figure 1-Source Data 1, Figure 3-Source Data 1 and Figure 5-Source Data 1-3 contain the source data for the respective figures

The following data sets were generated

Article and author information

Author details

  1. Maja Solman

    Hubrecht Institute-KNAW, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Sasja Blokzijl-Franke

    Hubrecht Institute-KNAW, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Florian Piques

    Hôpital Robert Debré, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Chuan Yan

    Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Qiqi Yang

    Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Marion Strullu

    Hôpital Robert Debré, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  7. Sarah M Kamel

    Hubrecht Institute-KNAW, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4424-9732
  8. Pakize Ak

    Hubrecht Institute-KNAW, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Jeroen Bakkers

    Cardiac Development and Genetics, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9418-0422
  10. David M Langenau

    Molecular Pathology Unit, Massachusetts General Hospital, Charlestown, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6664-8318
  11. Helene Cave

    Hôpital Robert Debré, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2840-1511
  12. Jeroen den Hertog

    Hubrecht Institute-KNAW, Utrecht, Netherlands
    For correspondence
    j.denhertog@hubrecht.eu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8642-8088

Funding

European Commission (ERARE NSEURONET)

  • Jeroen den Hertog

European Commission (EJPRD NSEURONET)

  • Helene Cave

European Commission (EJPRD NSEURONET)

  • Jeroen den Hertog

KWF Kankerbestrijding (12829)

  • Jeroen den Hertog

NIH Office of the Director (R01CA211734)

  • David M Langenau

NIH Office of the Director (R24OD016761)

  • David M Langenau

European Commission (ERARE NSEURONET)

  • Helene Cave

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All procedures involving experimental animals were approved by the animal experiments committee of the Royal Netherlands Academy of Arts and Sciences (KNAW), Dierexperimenten commissie protocol HI18-0702, and performed under the local guidelines in compliance with national and European law.

Human subjects: All children's samples were obtained after parents had given their written informed consent. Experiments were approved by the institutional review board of the French Institute of Health and Medical Research (INSERM) (IORG0003254) in accordance with the Helsinki declaration. Healthy children bone marrows were obtained from intrafamilial BM transplantation donors and used with the approval of the Institutional Review Board of "Hôpitaux Universitaires Paris Nord Val-de-Seine," Paris 7 University, AP-HP), (IRB: 00006477), in accordance with the Helsinki declaration.

Reviewing Editor

  1. Richard M White, Memorial Sloan Kettering Cancer Center, United States

Version history

  1. Preprint posted: September 10, 2020 (view preprint)
  2. Received: August 13, 2021
  3. Accepted: April 20, 2022
  4. Accepted Manuscript published: May 10, 2022 (version 1)
  5. Version of Record published: May 19, 2022 (version 2)

Copyright

© 2022, Solman 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. Maja Solman
  2. Sasja Blokzijl-Franke
  3. Florian Piques
  4. Chuan Yan
  5. Qiqi Yang
  6. Marion Strullu
  7. Sarah M Kamel
  8. Pakize Ak
  9. Jeroen Bakkers
  10. David M Langenau
  11. Helene Cave
  12. Jeroen den Hertog
(2022)
Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects
eLife 11:e73040.
https://doi.org/10.7554/eLife.73040

Share this article

https://doi.org/10.7554/eLife.73040

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