# STAT3R152W Mutation Model Reveals Temporal Changes in Hematopoietic Populations

## TL;DR

A mouse model of the STAT3R152W mutation shows changes in blood cell populations and immune function, but does not cause clear autoimmunity.

## Contribution

A novel mouse model reveals temporal and sex-specific hematopoietic changes caused by the STAT3R152W mutation.

## Key findings

- STAT3R152W mice show increased splenic Th17 cells and immune dysregulation.
- Mice exhibit anemia-like traits but increased thrombocytes, contradicting some clinical reports.
- Changes in hematopoietic populations vary over time and differ between males and females.

## Abstract

Inconsistent presentation of STAT3 variants in clinical settings makes them challenging to use in diagnostics and the prevention of unfavorable outcomes. Patients harboring the STAT3R152W 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 STAT3R152W 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 STAT3R152W variant as a cause of severe immune dysregulation, but only as a cofactor in the development of autoimmunity.