JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia
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, David B Sykes, 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, David B Sykes
Abstract
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-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.
Conclusions: 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: Funding was provided by the Massachusetts General Hospital Department of Medicine Pathways Program and NIH T32 AI007387. A trial registration is at https://ichgcp.net/clinical-trials-registry/NCT03906318.
Keywords: Aplastic anemia; JAK inhibition; JAK/STAT; STAT1 GOF; STAT1 gain-of-function; T-cell exhaustion; Translation to patients; autoimmune; interferon gamma; itacitinib.
Conflict of interest statement
Declaration of interests Y.-B.C. reports consulting fees from Incyte. A.K.S. reports compensation for consulting and/or SAB membership from FL82, Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Hovione, Third Rock Ventures, Ochre Bio, Relation Therapeutics, and Dahlia Biosciences. J.M.R. reports consulting fees from Third Rock Ventures. D.B.S. is a co-founder and holds equity in Clear Creek Bio, is a consultant and holds equity in SAFI Biosolutions, and is a consultant for Keros Therapeutics. A.R. is an advisory board member of Med, a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and, until August 31, 2020, was an SAB member of Syros Pharmaceuticals, Neogene Therapeutics, Asimov, and Thermo Fisher Scientific. From August 1, 2020, A.R. is an employee of Genentech. All other authors declare no competing interests.
Copyright © 2021 Elsevier Inc. All rights reserved.
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Source: PubMed