Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia

The prevalence and functional impact of somatic mutations in nonleukemic T cells is not well characterized, although clonal T-cell expansions are common. In immune-mediated aplastic anemia (AA), cytotoxic T-cell expansions are shown to participate in disease pathogenesis. We investigated the mutation profiles of T cells in AA by a custom panel of 2533 genes. We sequenced CD4+ and CD8+ T cells of 24 AA patients and compared the results to 20 healthy controls and whole-exome sequencing of 37 patients with AA. Somatic variants were common both in patients and healthy controls but enriched to AA patients’ CD8+ T cells, which accumulated most mutations on JAK-STAT and MAPK pathways. Mutation burden was associated with CD8+ T-cell clonality, assessed by T-cell receptor beta sequencing. To understand the effect of mutations, we performed single-cell sequencing of AA patients carrying STAT3 or other mutations in CD8+ T cells. STAT3 mutated clone was cytotoxic, clearly distinguishable from other CD8+ T cells, and attenuated by successful immunosuppressive treatment. Our results suggest that somatic mutations in T cells are common, associate with clonality, and can alter T-cell phenotype, warranting further investigation of their role in the pathogenesis of AA.

In:Leukemia: Springer Science and Business Media LLC35:75, s. 1365-13791476-55510887-6924

By the author/editor: Lundgren, S; Keranen, MAI; Kankainen, M; Huuhtanen, J; Walldin, G; Kerr, CM; show more...; Clemente, M; Ebeling, F; Rajala, H; Bruck, O; Lahdesmaki, H; Hannula, S; Hannunen, T; Ellonen, P; Young, NS; Ogawa, S; Maciejewski, JP; Hellstrom-Lindbe ...; Mustjoki, S; show less...

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