Utilization of JAK inhibitor therapy in a transplant model of STAT1 GOF disease

Project Abstract: The number of patients worldwide with severe immune dysregulation associated with STAT1 gain of function (GOF) disease is increasing due to genetic testing and early identification. There is moderate success with using Janus kinase inhibitors (JAKi)s in balancing immune cell function. However, hematopoietic stem cell transplant (HSCT) outcomes are not favorable with a high incidence of secondary graft failure. The utility of treatment with JAKi pre-transplant to improve outcomes is not clearly established. The central hypothesis is that impaired cytokine signaling leads to secondary graft failure in HSCT in STAT1GOF and this can be mitigated by pre-transplant JAKi treatment. In the first aim, we will evaluate the efficacy of JAKi inhibition pre- and post-transplant using a murine model of STAT1 GOF. We will treat STAT1 GOF recipient animals with JAKi before or after transplantation with WT bone marrow. By comparing the outcomes of those treated before versus after transplant we will identify effects of inflammation in the radioresistant bone marrow milieu that may persist after transplant. In the second aim, we will xenotransplant primary CD34+ cells from STAT1 GOF patients into NSG mice and study whether JAKi therapies affects their radiosensitivity and mitigation of inflammation related consequences. Single cell transcriptomics performed on these cells will be compared to transcriptional changes induced by STAT1 signaling that are known to affect stem cell niche localization, quiescence, cell division, and differentiation. These studies will reveal mechanisms by which hematopoiesis is impaired in STAT1 GOF patients and may lead to discovery of critical disease biomarkers or new avenues for therapy and improved transplant outcomes.