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

Jacob M Rosenberg; Joshua M Peters; Travis Hughes; Caleb A Lareau; Leif S Ludwig; Lucas R Massoth; Christina Austin-Tse; Heidi L Rehm; Bryan Bryson; Yi-Bin Chen; Aviv Regev; Alex K Shalek; Sarah M Fortune; David B Sykes

doi:10.1016/j.medj.2021.12.003

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.

Authors

Affiliations

¹ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA. Electronic address: jrosenberg2@mgh.harvard.edu.
² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
³ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴ Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Harvard Medical School, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁶ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Laboratory for Molecular Medicine, Partners Personalized Medicine, Cambridge, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁷ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁹ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Massachusetts General Hospital Cancer Center, Boston, MA, USA.
¹⁰ Broad Institute of MIT and Harvard, Cambridge, MA, USA; Genentech, South San Francisco, CA, USA.
¹¹ Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Institute for Medical Engineering and Science, Department of Chemistry, and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA; Broad Institute of MIT and Harvard, Cambridge, MA, USA.
¹² Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA, USA; Harvard Medical School, Boston, MA, USA; Harvard T.H. Chan School of Public Health, Boston, MA, USA.
¹³ Department of Medicine, Massachusetts General Hospital, Boston, MA 02114, USA; Center for Regenerative Medicine, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA; Massachusetts General Hospital Cancer Center, Boston, MA, USA. Electronic address: dbsykes@mgh.harvard.edu.

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.

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

Substances

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

Supplementary concepts

Aplastic anemia, idiopathic

Associated data

ClinicalTrials.gov/NCT03906318

Grants and funding

T32 AI007387/AI/NIAID NIH HHS/United States