Suchergebnisse

Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4 T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4 T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies. + + ; This work was supported by the European Research Council (M-IMM project), Academy of Finland (Decisions 287224, 314442), Finnish special governmental subsidy for health sciences, research and training, Sigrid Juselius Foundation, Instrumentarium Science foundation, Helsinki Institute of Life Sciences Fellow funding, Cancer Foundation Finland, and Finnish Cancer Institute. T.L. was supported by the Academy of Finland (Decisions 311081 and 314557). This study was supported by Finnish Functional Genomics Center, University of Turku, Åbo Akademi University and Biocenter Finland. IT Center for Science LTD (CSC) is acknowledged for their help and computing resources.