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

Abstract

SummaryThe 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.

Novel therapeutic perspectives in Noonan syndrome and RASopathies

“…A better understanding of the pathophysiology of NS and other RASopathies has also highlighted specific defects at the subcellular, cellular, or tissue levels that may represent potent targets for selective therapies. Thus, recent preclinical studies in mouse and zebrafish models of NS have shown constitutive inflammation as a driving force for metabolic impairment and haematological features [3], and treatment of zebrafish embryos with the antiinflammatory corticosteroid dexamethasone improved the JMML phenotype [48]. In addition, dysfunctions of mitochondrial bioenergetics and quality control have been identified in several RASopathies, including NS and Costello syndrome, that are causally linked to heart disease [49,50].…”