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Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia
- Lundgren, S (author)
- Keranen, MAI (author)
- Kankainen, M (author)
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- Huuhtanen, J (author)
- Walldin, G (author)
- Kerr, CM (author)
- Clemente, M (author)
- Ebeling, F (author)
- Rajala, H (author)
- Bruck, O (author)
- Lahdesmaki, H (author)
- Hannula, S (author)
- Hannunen, T (author)
- Ellonen, P (author)
- Young, NS (author)
- Ogawa, S (author)
- Maciejewski, JP (author)
- Mustjoki, S (author)
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- (creator_code:org_t)
- 2021-03-30
- 2021
- English.
- In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:115, s. 1365-1379
- Journal article (peer-reviewed)
Abstract
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- 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.
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- 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
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- Articles in the publication
- Leukemia
- By the university
- Karolinska Institutet
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