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

Autor: Satu Mustjoki, Pekka Ellonen, Eva Hellström-Lindberg, Hanna Rajala, Sofie Lundgren, Jaroslaw P. Maciejewski, Freja Ebeling, Cassandra M Kerr, Neal S. Young, Gunilla Walldin, Sari Hannula, Matti Kankainen, Jani Huuhtanen, Oscar Brück, Harri Lähdesmäki, Mikko A. I. Keränen, Seishi Ogawa, Tiina Hannunen, Michael J. Clemente
Přispěvatelé: University of Helsinki, Department of Computer Science, Karolinska Institutet, Cleveland Clinic Foundation, Computer Science Professors, National Institutes of Health, Kyoto University, Aalto-yliopisto, Aalto University, Department of Clinical Chemistry and Hematology, Faculty of Medicine, Hematologian yksikkö, HUS Comprehensive Cancer Center, Department of Oncology, TRIMM - Translational Immunology Research Program, HUSLAB, Department of Medical and Clinical Genetics, Helsinki University Hospital Area, Institute for Molecular Medicine Finland, Helsinki Institute of Life Science HiLIFE, Digital Precision Cancer Medicine (iCAN)
Rok vydání: 2020
Předmět:
Zdroj: Leukemia
ISSN: 1476-5551
Popis: Funding Information: Acknowledgements The authors would like to thank Hanna Läh-teenmäki, Tiina Kasanen, and Jay Klievink from the Hematology Research Unit Helsinki for valuable technical assistance. The authors would also like to thank Noora Aarnio from the Biomedicum Flow Cytometry for her expertise and assistance with cell sorting. Jenni Lahtela and Emma Saarinen from Technology Centre of Institute of Molecular Medicine Finland (FIMM) are acknowledged for their excellent work on single-cell sequencing. Single-cell sequencing, immunogene panel sequencing, and skin sample WES were performed at FIMM Single-cell Analytics and Sequencing units, which are supported by HiLIFE and Biocenter Finland. The authors acknowledge Finnish Red Cross Blood Service for providing healthy control samples. The authors acknowledge Helsinki Biobank for providing bone marrow biopsies and the Finnish Hematology Registry and Clinical Biobank (FHRB) for providing MNC samples of AA patients. The authors thank all the patients for their generous participation. The FHRB Biobank is supported by the Finnish Association of Funding Information: Hematology, Finnish Red Cross Blood Service, Institute for Molecular Medicine Finland, and participating hospitals in Finland. The authors acknowledge IT Center for Science Ltd for data storage and computational resources and the computational resources provided by the Aalto Science-IT project. The research was funded with research grants from the European Research Council (M-IMM and STRATIFY projects), Academy of Finland, Sigrid Juselius Foundation, Cancer Foundation Finland, Blood Disease Research Foundation, and Instrumentarium Science Foundation. Publisher Copyright: © 2021, The Author(s). Copyright: Copyright 2021 Elsevier B.V., All rights reserved. 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.
Databáze: OpenAIRE
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