Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects
- Hubrecht Institute-KNAW, Netherlands
- Hôpital Robert Debré, France
- Massachusetts General Hospital, United States
- 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
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Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndromeNCBI Gene Expression Omnibus, GSE167787.
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Inflammatory response in HSPC of PTPN11-mutated JMMLNCBI Gene Expression Omnibus, GSE183252.
Article and author information
Author details
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.
Reviewing Editor
- Richard M White, Memorial Sloan Kettering Cancer Center, United States
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.
Version history
- Preprint posted: September 10, 2020 (view preprint)
- Received: August 13, 2021
- Accepted: April 20, 2022
- Accepted Manuscript published: May 10, 2022 (version 1)
- 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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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
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