Background/Purpose: STAT3 gain-of-function (GOF) syndrome is a rare inborn error of immunity that leads to early-onset lymphoproliferation, autoimmune cytopenias, multi-solid organ autoimmunity, hypogammaglobulinemia, and short stature. Approximately one-fifth of individuals with STAT3 GOF develop inflammatory arthritis. STAT3 GOF syndrome results from heterozygous variants inSTAT3, an important transcription factor in numerous immune and non-immune cytokine signaling pathways. Investigating naturally occurring variants in STAT3 can shed light on numerous cellular processes given the critical roles for STAT3 in development, differentiation and regulation.

Methods: STAT3 GOF was determined using a standardized luciferase assay. Inhibition was assessed in patient-derived cell lines by reduction ofSOCS3transcript, as determined by quantitative real time PCR, in the presence of an inhibitor following stimulation with interleukin-21.

Results: There are 211 patients with STAT3 GOF syndrome caused by 84 unique mutations spanning the 6 domains of the molecule. There are 70 patients with 37 different mutations in the DNA binding domain, although the 3 most common mutations are in the coiled-coil (R152W) and transactivation (P715L and T716M) domains. The average relative potency of STAT3 GOF mutations at baseline is 28.5-fold above the transcriptional capacity of wild-type (WT) STAT3; however the range is 1.1- to 99.7-fold higher. Mutations that are not GOF at baseline, are GOF with cytokine stimulation. Unlike STAT3 mutations associated with the primary immunodeficiency autosomal-dominant hyper-IgE syndrome, STAT3 GOF mutations are not dominant to WT. Intriguingly, some, but not all, STAT3 GOF mutations do not require phosphorylation at the canonical tyrosine 705 amino acid to drive transcription at higher than WT rates. Other STAT3 GOF mutations appear to be tempered by serine 727 phosphorylation. All tested STAT3 GOF mutations were effectively inhibited by the JAK inhibitors ruxolitinib, tofacitinib, and/or baricitinib. The direct STAT3 inhibitor S3I-201 reducedSOCS3

transcription by approximately 50% in control cells, and also in several of the STAT3 GOF cell lines tested.

Conclusion: We determined the relative potency of all known disease-associated STAT3 GOF variants. Fortunately, JAK inhibitors are effective against all tested STAT3 GOF variants and should be considered for targeted treatment of patients with STAT3 GOF syndrome. Work to elucidate the cellular mechanisms of STAT3 GOF variants is ongoing.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stat3-gain-of-function-syndrome-mutations-are-susceptible-to-jak-inhibition-despite-a-spectrum-of-potency/