Item Type: | Article |
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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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