Exploring Experimental Hematology: May 2024 (Volume 133)
Cora C.A. Beckmann, Senthilkumar Ramamoorthy, Eirini Trompouki, Wolfgang Driever, Stephan Schwarz-Furlan, Brigitte Strahm, Ayami Yoshimi, Charlotte M. Niemeyer, Miriam Erlacher, Friedrich G. Kapp
Myeloproliferative neoplasms (MPNs) and myelodysplastic syndrome (MDS) are rare hematologic disorders in children that can only be cured by hematopoietic stem cell transplantation (HSCT). The genetics of pediatric MPN and MDS are only partially understood and are extrapolated from epidemiologic studies in older adults. RAS pathway mutations often occur in pediatric MPN and MDS, and children with predisposition for these conditions often bear germline mutations in components of the RAS signaling pathway. Led by Dr. Kapp at the Faculty of Medicine, University of Freiburg, the authors describe a 2-year-old patient with pancytopenia, massive splenomegaly with myeloid and erythroid precursors in the peripheral blood. Given that the initial presentation resembled juvenile myelomonocytic leukemia (JMML), RAS pathway genes were analyzed, which revealed a tandem in frame duplication of NRAS (c.192_227dup; p.G75_E76insD65G75) of questionable pathogenicity, since most pathogenic mutations in NRAS as amino acid substitutions occurring at critical hotspots. The patient underwent cytoreductive chemotherapy and a myeloablative HSCT, but unfortunately succumbed to treatment-related complications.
Despite this outcome, the authors endeavored to understand the functional impact of such RAS pathway mutations on hematopoiesis using the zebrafish as a model system. They cloned the NRAS mutation and injected the vector into zebrafish embryos using an endothelial cell/blood stem and progenitor cell-specific promoter system for ectopic expression. They also cotransfected transposase to facilitate integration of the NRAS vector. Ectopic expression of the variant NRAS resulted in an MPN-like phenotype in zebrafish blood stem and progenitor cells. Indeed, the NRAS duplication variant had a stronger MPN-like phenotype in this system compared to known NRAS activating amino acid substitutions. Finally, the authors showed that treatment with a MEK inhibitor could mitigate the MPD phenotype. Overall, this study demonstrates an approach to rapidly functionally validate the consequences of RAS pathway variants on the activity of blood stem cells in vivo and is conducive to efficient identification of effective personalized therapies.
Blog post contributed by R. Grant Rowe, MD, PhD, ISEH Publications Committee Chair
Please note that the statements made by Simply Blood Authors are their own views and not necessarily the views of ISEH. ISEH disclaims any or all liability arising from any author's statements or materials.
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