Instructor Harvard Medical School Boston, Massachusetts, United States
Abstract Text: Authors: Jacob M. Rosenberg, Joshua M. Peters, Travis Hughes, Caleb A. Lareau, Leif S. Ludwig, Lucas R. Massoth, Christina Austin-Tse, Heidi L. Rehm, Bryan Bryson, Yi-Bin Chen, Aviv Regev, Alex K. Shalek, Sarah M. Fortune, and David B. Sykes.
Background: 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.
Methods: 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.
Findings: Following therapy, samples showed a decrease in the plasma concentration of interferon-g, a decrease in PD-1 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 hyperactivation.
Conclusions: These findings raise the possibility that STAT1 hyperactivation defines a subset of idiopathic aplastic anemia patients for whom JAK inhibition may be an efficacious therapy.
