PUBLICATION

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

Authors
Solman, M., Blokzijl-Franke, S., Piques, F., Yan, C., Yang, Q., Strullu, M., Kamel, S.M., Ak, P., Bakkers, J., Langenau, D.M., Cave, H., den Hertog, J.
ID
ZDB-PUB-220511-5
Date
2022
Source
eLIFE   11: (Journal)
Registered Authors
Bakkers, Jeroen, den Hertog, Jeroen, Langenau, David
Keywords
cancer biology, developmental biology, zebrafish
MeSH Terms
  • Animals
  • Hematopoietic Stem Cells/metabolism
  • Humans
  • Leukemia, Myelomonocytic, Juvenile*/genetics
  • Leukemia, Myelomonocytic, Juvenile*/metabolism
  • Mutation
  • Noonan Syndrome*/genetics
  • Noonan Syndrome*/metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics*
  • Zebrafish
PubMed
35535491 Full text @ Elife
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes