JAK-STAT signaling in human disease: From genetic syndromes to clinical inhibition

• Published in: Journal of allergy and clinical immunology Vol. 148; no. 4; pp. 911 - 925
• Main Authors: Luo, Yiming, Alexander, Madison, Gadina, Massimo, O’Shea, John J., Meylan, Francoise, Schwartz, Daniella M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-10-2021
• Subjects: Animals; Cytokines - immunology; Genetic Diseases, Inborn - drug therapy; Genetic Diseases, Inborn - immunology; Humans; immunodeficiency; immunomodulation; JAK; Jakinib; Janus Kinase Inhibitors - therapeutic use; Janus Kinases - genetics; Janus Kinases - immunology; Mutation; Signal Transduction; STAT; STAT Transcription Factors - genetics; STAT Transcription Factors - immunology; immunomodulation; FDA; LOF; AD; IBD; MPN; SCID; SLE; HIES; UC; RA; COVID-19; γc; STAT; SNP; JAK; MF; Jakinib; immunodeficiency; ISG; NK; GOF; PsA
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2021.08.004

Since its discovery, the Janus kinase-signal transduction and activation of transcription (JAK-STAT) pathway has become recognized as a central mediator of widespread and varied human physiological processes. The field of JAK-STAT biology, particularly its clinical relevance, continues to be shaped by 2 important advances. First, the increased use of genomic sequencing has led to the discovery of novel clinical syndromes caused by mutations in JAK and STAT genes. This has provided insights regarding the consequences of aberrant JAK-STAT signaling for immunity, lymphoproliferation, and malignancy. In addition, since the approval of ruxolitinib and tofacitinib, the therapeutic use of JAK inhibitors (jakinibs) has expanded to include a large spectrum of diseases. Efficacy and safety data from over a decade of clinical studies have provided additional mechanistic insights while improving the care of patients with inflammatory and neoplastic conditions. This review discusses major advances in the field, focusing on updates in genetic diseases and in studies of clinical jakinibs in human disease.