Inflammation potentiates JMML-like blood defects in Shp2 mutant Noonan syndrome

The RASopathy Noonan syndrome (NS) is a frequent developmental disorder predominantly caused by activating mutations in the phosphatase SHP2. Among other features, NS children are predisposed to develop juvenile myelomonocytic leukemia (JMML). We developed a zebrafish mutant line carrying the NS-patient associated mutation Shp2-D61G. Shp2D61G zebrafish recapitulate major NS traits, including a JMML-like phenotype originating from defective hematopoietic stem and progenitor cells (HSPCs). Single cell RNA sequencing of mutant HSPCs revealed expansion of monocyte/macrophage progenitor cells associated with developmentally regulated cytokine production and elevated inflammation. Importantly, an anti-inflammatory agent rescued the JMML-like phenotype. Our results reveal a role for developmentally-induced inflammation in genesis of NS/JMML blood phenotypes and suggest anti-inflammatory drugs as potential new therapies.