Browsing by Author "Lundgren, Sofie Alexandra"

The role of somatic mutations in cancer development is undisputable, but our knowledge of the prevalence and function of somatic mutations in healthy cells is yet unresolved question. In immune-mediated bone-marrow failure (such as aplastic anemia and hypoplastic myelodysplastic syndromes) hematopoietic stem cells are destroyed by cytotoxic T cells, which have been shown to be oligoclonal and in some cases harbor STAT3 mutations. We addressed clonality of non-malignant T cells by investigating somatic mutations with a custom- made gene panel of 2533 genes. We sequenced CD4+ and CD8+ cells of 29 patients with immune-mediated bone marrow failure and compared the results to 20 healthy controls as well as previously published data on patients with aplastic anemia. Somatic variants in lymphocytes were common both in patients and healthy controls, but especially enriched in aplastic anemia patients and CD8+ T cells. CD8+ T cells of aplastic anemia patients accumulated most mutations on JAK-STAT and MAPK pathways. The number of somatic mutations was associated with CD8+ T cell clonality, assessed by T cell receptor beta sequencing. To further understand the role of mutations in T cells, we performed single-cell RNA sequencing from 6 longitudinal samples of 2 aplastic anemia patients with STAT3, KRAS, NFATC2 and PTPN22 mutations in CD8+ T cell clones. Mutated clones showed cytotoxic phenotype, which was altered by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality and may alter T cell phenotype. The role of somatic mutations in the initiation and persistence of autoreactive clones needs to be further investigated.