Somatic mutations in lymphocytes in patients with immune-mediated aplastic anemia.
Sofie A LundgrenMikko A I KeränenMatti KankainenJani HuuhtanenGunilla WalldinCassandra M KerrMichael ClementeFreja EbelingHanna RajalaOscar BrückHarri LähdesmäkiSari HannulaTiina HannunenPekka EllonenNeal S YoungSeishi OgawaJaroslaw P MaciejewskiEva Hellström-LindbergMohamed El MissiryPublished in: Leukemia (2021)
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.
Keyphrases
- end stage renal disease
- chronic kidney disease
- newly diagnosed
- ejection fraction
- single cell
- peritoneal dialysis
- prognostic factors
- oxidative stress
- copy number
- signaling pathway
- cell proliferation
- risk factors
- genome wide
- gene expression
- acute lymphoblastic leukemia
- transcription factor
- allogeneic hematopoietic stem cell transplantation
- high resolution
- smoking cessation
- peripheral blood
- binding protein
- combination therapy
- atomic force microscopy