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

Sofie Lundgren*, Mikko A.I. Keränen, Matti Kankainen, Jani Huuhtanen, Gunilla Walldin, Cassandra M. Kerr, Michael Clemente, Freja Ebeling, Hanna Rajala, Oscar Brück, Harri Lähdesmäki, Sari Hannula, Tiina Hannunen, Pekka Ellonen, Neal S. Young, Seishi Ogawa, Jaroslaw P. Maciejewski, Eva Hellström-Lindberg, Satu Mustjoki

*Corresponding author for this work

Research output: Contribution to journalArticleScientificpeer-review

6 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1365-1379
Number of pages15
Issue number5
Early online date2021
Publication statusPublished - May 2021
MoE publication typeA1 Journal article-refereed


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