Inherited STAT3 mutation mediates familial autoimmune disease, leukemogenesis, and responses to immunomodulator

Germline activating mutations in STAT3 result in immune dysregulation, autoimmunity, and increased malignancy risk, yet the precise molecular mechanisms underlying disease heterogeneity remain unclear. We identified a familial germline STAT3 p.R278H mutation shared between the parent diagnosed with T-cell large granular lymphocytic leukemia and the proband presenting with infantile-onset multisystem autoimmune disease-1. Employing whole-exome sequencing, single-cell RNA sequencing, comprehensive cytokine profiling, and flow cytometry-based immunophenotyping, we characterized their distinct clinical phenotypes and underlying immune dysregulation. Single-cell transcriptomics revealed marked expansion of CD8+ T cells in the proband, accompanied by altered expression of JAK/STAT pathway genes, including elevated STAT3, STAT1, and downstream target genes (BATF, MAF, MYC), but diminished cytokine transcripts (IL1B, TNF). Serum cytokines, however, were markedly elevated, highlighting discordant transcriptional and translational regulation. The parent exhibited additional somatic mutations, notably FLT3-ITD, suggesting a multi-hit model underpinning leukemogenesis rather than direct oncogenic transformation by STAT3 alone. Immunomodulatory therapies, including cyclosporin A and tacrolimus, controlled autoimmune symptoms in the proband, whereas the parent was refractory to conventional treatments, ultimately succumbing after unsuccessful hematopoietic stem cell transplantation. Our findings emphasize that germline STAT3 activating mutations predispose individuals to complex immune dysregulation and require additional somatic mutations to initiate overt malignancy. This study supports comprehensive genetic profiling and precision medicine approaches for patients harboring congenital STAT3 mutations, aiming to optimize clinical management and improve therapeutic outcomes.