STAT3R152W Mutation Model Reveals Temporal Changes in Hematopoietic Populations

Inconsistent presentation of <i>STAT3</i> variants in clinical settings makes them challenging to use in diagnostics and the prevention of unfavorable outcomes. Patients harboring the <i>STAT3^R152W</i> variant display a range of autoimmune disorders, including type 1 diabetes, hemolytic anemia, and thrombocytopenia. Because of a complex interplay of genetic and environmental cofactors, it is difficult to discern the direct role STAT3 plays in the development of those conditions. Here, we report a mouse model of the <i>STAT3^R152W</i> variant and describe its hematopoietic populations throughout adulthood. We observed profound changes in both innate and adaptive immunity, including increased splenic Th17 component consistent with a gain-of-function mutation, as described in the literature. At the same time, the mice did not develop obvious symptoms of autoimmunity. R152W mutants show lowered hemoglobin and hematocrit, indicating susceptibility to anemia, but also an increased number of thrombocytes, contradictory to reports of autoimmune thrombocytopenia. We showcase how those changes develop and wane in time, and the differences between male and female animals. Our findings paint the <i>STAT3^R152W</i> variant as a cause of severe immune dysregulation, but only as a cofactor in the development of autoimmunity.