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

Item Type:Article
Title:JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia
Creators Name:Rosenberg, J.M. and Peters, J.M. and Hughes, T. and Lareau, C.A. and Ludwig, L.S. and Massoth, L.R. and Austin-Tse, C. and Rehm, H.L. and Bryson, B. and Chen, Y.B. and Regev, A. and Shalek, A.K. and Fortune, S.M. and Sykes, D.B.
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-?, 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.
Keywords:Aplastic Anemia, Autoimmune, STAT1 GOF, STAT1 Gain-of-Function, Itacitinib, JAK Inhibition, JAK/STAT, T-Cell Exhaustion, Interferon Gamma
Source:Med
ISSN:2666-6340
Publisher:Elsevier
Volume:3
Number:1
Page Range:42-57.e5
Date:14 January 2022
Additional Information:Copyright © 2021 Elsevier Inc. All rights reserved.
Official Publication:https://doi.org/10.1016/j.medj.2021.12.003
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed

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