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
Datasets
GEO:GSE167787
MeSH Terms
  • Hematopoietic Stem Cells/metabolism
  • Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics*
  • Humans
  • Leukemia, Myelomonocytic, Juvenile*/genetics
  • Leukemia, Myelomonocytic, Juvenile*/metabolism
  • Zebrafish
  • Mutation
  • Animals
  • Noonan Syndrome*/genetics
  • Noonan Syndrome*/metabolism
(all 10)
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
Figure Gallery (10 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
dhu12562
    		MNV
    fb103
      		Small Deletion
      gl23TgTransgenic Insertion
        hu5920
          		Point Mutation
          i114TgTransgenic Insertion
            la2TgTransgenic Insertion
              s916TgTransgenic Insertion
                sh445TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  ptpn11aCRISPR3-ptpn11aCRISPR
                  1 - 1 of 1
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                  Fish
                  No data available
                  Antibodies
                  No data available
                  Orthology
                  No data available
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  EGFPEFGEGFP
                  GFPEFGGFP
                  mCherryEFGmCherry
                  1 - 3 of 3
                  Show
                  Mapping
                  No data available
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                  Citation
                  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. (2022) Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects. eLIFE. 11:.