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

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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., Peters, J.M., Hughes, T., Lareau, C.A., Ludwig, L.S., Massoth, L.R., Austin-Tse, C., Rehm, H.L., Bryson, B., Chen, Y.B., Regev, A., Shalek, A.K., 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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