JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia

Idiopathic aplastic anemia is a potentially lethal disease, characterized by T cell-mediated autoimmune attack of bone marrow hematopoietic stem cells. Standard of care therapies (stem cell transplantation or immunosuppression) are effective but associated with a risk of serious toxicities. An 18-year-old man presented with aplastic anemia in the context of a germline gain-of-function variant in STAT1. Treatment with the JAK1 inhibitor itacitinib resulted in a rapid resolution of aplastic anemia and a sustained recovery of hematopoiesis. Peripheral blood and bone marrow samples were compared before and after JAK1 inhibitor therapy. Following therapy, samples showed a decrease in the plasma concentration of interferon-γ, a decrease in PD1-positive exhausted CD8+ T cell population, and a decrease in an interferon responsive myeloid population. Single-cell analysis of chromatin accessibility showed decreased accessibility of STAT1 across CD4+ and CD8+ T cells, as well as CD14+ monocytes. To query whether other cases of aplastic anemia share a similar STAT1-mediated pathophysiology, we examined a cohort of 9 patients with idiopathic aplastic anemia. Bone marrow from six of nine patients also displayed abnormal STAT1 hyper-activation. These findings raise the possibility that STAT1 hyperactivition defines a subset of idiopathic aplastic anemia patients for whom JAK inhibition may be an efficacious therapy. Funding was provided by the Massachusetts General Hospital Department of Medicine Pathways Program and NIH T32 AI007387. A trial registration is at https://clinicaltrials.gov/ct2/show/NCT03906318. [Display omitted] A patient with a germline STAT1 GOF variant presented with aplastic anemiaAplastic anemia resolved following treatment with itacitinib, a JAK1 inhibitorAn exhausted CD8+ T cell population correlated with disease activityBone marrow STAT1 activation was also found in other idiopathic aplastic anemia cases Aplastic anemia is a potentially lethal autoimmune disease where the immune system erroneously targets and destroys bone marrow stem cells. Treatments such as immunosuppression or bone marrow transplantation are effective but have serious side effects. A patient presented to our hospital with aplastic anemia due to a mutation in STAT1, a gene involved in immune system function. Patients with other conditions caused by STAT1 mutations have been successfully treated with JAK inhibitors—a class of medications associated with fewer side effects. Our pa