The spectrum of somatic mutations in large granular lymphocyte leukemia, rheumatoid arthritis, and Felty's syndrome

Funding Information: PS was supported by Blood Research Foundation and HUS Diagnostic Center. DB was supported by the Doctoral Programme in Clinical Research. JH was supported by Finnish Hematology Association, Blood Disease Research Foundation, Helsinki Institute for Life Science, Biomedicum Helsinki Foundation, Finnish Medical Foundation, K. Albin Johansson Foundation, Kaute Foundation, Suomalais-Norjalainen Lääketieteen Säätiö and Emil Aaltonen Foundation. Publisher Copyright: © 2022 Elsevier Inc.T cell large granular lymphocyte leukemia (T-LGLL) is an interesting case at the intersection of autoimmunity and cancer. In T-LGLL, T cells with somatic pathogenic mutations (mainly in STAT3) are linked to rheumatoid arthritis (RA) and neutropenia. A rare subtype of RA, Felty's syndrome, exhibits overlapping clinical features and comparable frequencies of activating STAT3 mutations in T cells as T-LGLL, which hints at a potential T-LGLL–Felty's syndrome–RA axis. Somatic mutations could shed light on the unexplained pathologies of these disorders. However, the causality of somatic mutations–do somatic mutations in immune cells cause inflammation, or does prolonged inflammation predispose to mutagenesis–remains unanswered. This review will focus on the recent advances in understanding somatic mutations in T-LGLL and related autoimmune conditions as a master regulatory network that sustains lymphoproliferation and inflammation.Peer reviewe