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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 Shp2Juvenile myelomonocytic leukaemia is a childhood blood cancer. It is more common in children with a genetic condition called Noonan Syndrome, which causes problems with development in many parts of the body. The most frequent cause is a mutation in a protein called Src homology region 2 domain-containing phosphatase-2, or SHP2 for short. Juvenile myelomonocytic leukaemia starts in the stem cells that normally become blood cells. In children with Noonan Syndrome, these cells show signs of problems before leukaemia begins. Recreating Noonan Syndrome in an animal could shed light on how this childhood cancer develops, but doing this is not straightforward. One option is to use zebrafish, a species of fish in which the embryos are transparent, allowing scientists to watch their blood cells developing under a microscope. They also share many genes with humans, including SHP2. Solman et al. genetically modified zebrafish so they would carry one of the most common mutations seen in children with Noonan Syndrome in the SHP2 protein. The fish had many of the typical features of the condition, including problems producing blood cells. Single cell analysis of the stem cells that become these blood cells showed that, in the mutated fish, these cells had abnormally high levels of activity in genes involved in inflammation. Treating the fish with an anti-inflammatory drug, dexamethasone, reversed the problem. When Solman et al. investigated stem cells from human patients with juvenile myelomonocytic leukaemia, they found the same high levels of activity in inflammatory genes. The current treatment for juvenile myelomonocytic leukaemia is a stem cell transplant, which is only successful in around half of cases. Finding a way to prevent the cancer from developing altogether could save lives. This new line of zebrafish allows researchers to study Noonan Syndrome in more detail, and to test new treatments. A next step could be to find out whether anti-inflammatory drugs have the same effects in mammals as they do in fish.

To investigate whether ontogeny-related features determine the pediatric specificity in juvenile myelomonocytic leukemia (JMML), we compared the gene expression profile of hematopoietic progenitor cells sorted from JMML to their healthy counterparts isolated at different stages of ontogeny. Two groups of JMML were identified. The JMML in the first group had a fetal-like expression profile. Their progenitors showed a stronger monocytic identity than other JMML or healthy postnatal progenitors with overexpression of monocytic/dendritic, inflammasome and innate immunity markers, reminiscent of the monocyte-biased myelopoiesis characterizing physiologic fetal hematopoiesis. The second group, although clustering apart from healthy prenatal and post-natal fractions, was characterized by aberrant expression of the master oncofetal regulator LIN28B, suggesting developmental dysregulation. LIN28B expression was associated with DNA hypermethylation. Analysis of a large cohort of 108 patients with JMML showed that a high LIN28 expression was correlated to a poor outcome. Our findings highlight a strong but complex link between JMML and development, and will be important to guide future treatment strategies in this rare but severe leukemia.