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Somatic mutations i...
Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia
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Lundgren, S (author)
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Keranen, MAI (author)
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Kankainen, M (author)
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Huuhtanen, J (author)
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Walldin, G (author)
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Kerr, CM (author)
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Clemente, M (author)
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Ebeling, F (author)
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Rajala, H (author)
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Bruck, O (author)
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Lahdesmaki, H (author)
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Hannula, S (author)
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Hannunen, T (author)
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Ellonen, P (author)
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Young, NS (author)
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Ogawa, S (author)
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Maciejewski, JP (author)
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- Hellstrom-Lindberg, E (author)
- Karolinska Institutet
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Mustjoki, S (author)
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(creator_code:org_t)
- 2021-03-30
- 2021
- English.
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In: Leukemia. - : Springer Science and Business Media LLC. - 1476-5551 .- 0887-6924. ; 35:75, s. 1365-1379
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https://www.nature.c...
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http://kipublication...
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https://doi.org/10.1...
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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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- art (subject category)
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Leukemia
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- By the author/editor
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Lundgren, S
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Keranen, MAI
-
Kankainen, M
-
Huuhtanen, J
-
Walldin, G
-
Kerr, CM
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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 ...
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Mustjoki, S
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show less...
- Articles in the publication
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Leukemia
- By the university
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Karolinska Institutet