Nf1 and Sh2b3 mutations cooperate in vivo in a mouse model of juvenile myelomonocytic leukemia

• Published in: Blood advances 2021-09, Vol.5 (18), p.3587-3591
• Main Authors: Morales, Carolina E., Stieglitz, Elliot, Kogan, Scott C., Loh, Mignon L., Braun, Benjamin S.
• Format: Article
• Language: English
• Subjects: Animals; Child, Preschool; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Juvenile - genetics; Leukemia, Myelomonocytic, Juvenile - therapy; Mice; Mutation; Prognosis; Signal Transduction; Stimulus Report
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2020003754

Juvenile myelomonocytic leukemia (JMML) is initiated in early childhood by somatic mutations that activate Ras signaling. Although some patients have only a single identifiable oncogenic mutation, others have 1 or more additional alterations. Such secondary mutations, as a group, are associated with an increased risk of relapse after hematopoietic stem cell transplantation or transformation to acute myeloid leukemia. These clinical observations suggest a cooperative effect between initiating and secondary mutations. However, the roles of specific genes in the prognosis or clinical presentation of JMML have not been described. In this study, we investigate the impact of secondary SH2B3 mutations in JMML. We find that patients with SH2B3 mutations have adverse outcomes, as well as higher white blood cell counts and hemoglobin F levels in the peripheral blood. We further demonstrate this interaction in genetically engineered mice. Deletion of Sh2b3 cooperates with conditional Nf1 deletion in a dose-dependent fashion. These studies illustrate that haploinsufficiency for Sh2b3 contributes to the severity of myeloproliferative disease and provide an experimental system for testing treatments for a high-risk cohort of JMML patients. •SH2B3 mutations in JMML are associated with more aggressive disease in humans and Nf1 Sh2b3-mutant mice.•This novel mouse model provides a platform for studying the biology and therapy of high-risk JMML. [Display omitted]