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

Med. 2022 Jan 14;3(1):42-57.e5. doi: 10.1016/j.medj.2021.12.003.


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.

Keywords: Aplastic anemia; JAK inhibition; JAK/STAT; STAT1 GOF; STAT1 gain-of-function; T-cell exhaustion; Translation to patients; autoimmune; interferon gamma; itacitinib.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetonitriles
  • Adolescent
  • Anemia, Aplastic* / genetics
  • CD8-Positive T-Lymphocytes
  • Gain of Function Mutation
  • Humans
  • Janus Kinase Inhibitors* / pharmacology
  • Male
  • Pyrazoles
  • Pyrimidines
  • Pyrroles
  • STAT1 Transcription Factor / genetics


  • Acetonitriles
  • Janus Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Pyrroles
  • STAT1 Transcription Factor
  • STAT1 protein, human
  • itacitinib

Supplementary concepts

  • Aplastic anemia, idiopathic

Associated data

  • ClinicalTrials.gov/NCT03906318