Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function

Shuya Kaneko; Fumiaki Sakura; Kay Tanita; Asami Shimbo; Ryusuke Nambu; Masashi Yoshida; Shuichiro Umetsu; Ayano Inui; Chizuru Okada; Miyuki Tsumura; Mamiko Yamada; Hisato Suzuki; Kenjiro Kosaki; Osamu Ohara; Masaki Shimizu; Tomohiro Morio; Satoshi Okada; Hirokazu Kanegane

doi:10.1093/immadv/ltad027

Janus kinase inhibitors ameliorate clinical symptoms in patients with STAT3 gain-of-function

Immunother Adv. 2023 Nov 24;3(1):ltad027. doi: 10.1093/immadv/ltad027. eCollection 2023.

Authors

Shuya Kaneko¹, Fumiaki Sakura², Kay Tanita¹, Asami Shimbo¹, Ryusuke Nambu³, Masashi Yoshida³, Shuichiro Umetsu⁴, Ayano Inui⁴, Chizuru Okada⁵, Miyuki Tsumura², Mamiko Yamada⁶, Hisato Suzuki⁶, Kenjiro Kosaki⁶, Osamu Ohara⁷, Masaki Shimizu¹, Tomohiro Morio¹, Satoshi Okada², Hirokazu Kanegane⁸

Affiliations

¹ Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
² Department of Pediatrics, Hiroshima University Graduate School of Biomedical and Health Sciences, Hiroshima, Japan.
³ Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan.
⁴ Department of Pediatric Hepatology and Gastroenterology, Saiseikai Yokohama-shi Tobu Hospital, Kanagawa, Japan.
⁵ Hiroshima Chuodori Children Clinic, Hiroshima, Japan.
⁶ Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan.
⁷ Department of Technology Development, Kazusa DNA Research Institute, Chiba, Japan.
⁸ Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.

Abstract

Germline gain-of-function (GOF) variants in the signal transducer and activator of transcription 3 (STAT3) gene is an inborn error of immunity presenting with autoimmunity and lymphoproliferation. Symptoms can vary widely, and no effective treatment has been established. This study investigated the efficacy of Janus kinase (JAK) inhibitors (JAKi) in patients with STAT3-GOF. Four patients were enrolled and their clinical symptoms before and after the initiation of treatment with JAKi were described. A cell stimulation assay was performed using Epstein-Barr virus transformed lymphoid cell lines (EBV-LCLs) that were derived from the patients with STAT3-GOF. The patients presented with various symptoms, and these symptoms mostly improved after the initiation of JAKi treatment. Upon interleukin-6 stimulation, the EBV-LCLs of patients showed enhanced STAT3 phosphorylation compared with those of the EBV-LCLs of healthy controls. In conclusion, four Japanese patients with STAT3-GOF were successfully treated with JAKi. JAKi ameliorated various symptoms and therefore, the use of JAKi could be an effective treatment option for patients with STAT3-GOF.

Keywords: Janus kinase inhibitor; gain-of-function; lymphoblastoid cell lines; ruxolitinib; signal transducer and activator of transcription 3; tofacitinib.