JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia
Name
nihms-1767358.pdf
Description
Accepted version
Size
2.45 MB
Format
Adobe PDF
Checksum (MD5)
592887a05f224fe960a57f3c8cf6a02d
Author(s)
Rosenberg, Jacob M
Peters, Joshua M
Hughes, Travis
Lareau, Caleb A
Ludwig, Leif S
Massoth, Lucas R
Austin-Tse, Christina
Rehm, Heidi L
Bryson, Bryan
Chen, Yi-Bin
Date Issued
2022
Journal
Med
Publisher
Elsevier BV
Citation
Rosenberg, Jacob M, Peters, Joshua M, Hughes, Travis, Lareau, Caleb A, Ludwig, Leif S et al. 2022. "JAK inhibition in a patient with a STAT1 gain-of-function variant reveals STAT1 dysregulation as a common feature of aplastic anemia." Med, 3 (1).
Version
Author's final manuscript
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://clinicaltrials.gov/ct2/show/NCT03906318.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution-NonCommercial-NoDerivs License
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DOI of Published Version
https://doi.org/10.1016/J.MEDJ.2021.12.003
