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Kim, Daehong; Park, Giljun; Huuhtanen, Jani; Lundgren, Sofie; Khajuria, Rajiv K; Hurtado, Ana M; Muñoz-Calleja, Cecilia; Cardeñoso, Laura; Gómez-García de Soria, Valle; Chen-Liang, Tzu Hua; Eldfors, Samuli; Ellonen, Pekka; Hannula, Sari; Kankainen, Matti; Bruck, Oscar; Kreutzman, Anna; Salmenniemi, Urpu; Lönnberg, Tapio; Jerez, Andrés; Itälä-Remes, Maija; Myllymäki, Mikko; Keränen, Mikko A I; Mustjoki, Satu
Nature communications, 05/2020, Letnik: 11, Številka: 1Journal Article
Graft versus host disease (GvHD) is the main complication of allogeneic hematopoietic stem cell transplantation (HSCT). Here we report studies of a patient with chronic GvHD (cGvHD) carrying persistent CD4 T cell clonal expansion harboring somatic mTOR, NFKB2, and TLR2 mutations. In the screening cohort (n = 134), we detect the mTOR P2229R kinase domain mutation in two additional cGvHD patients, but not in healthy or HSCT patients without cGvHD. Functional analyses of the mTOR mutation indicate a gain-of-function alteration and activation of both mTORC1 and mTORC2 signaling pathways, leading to increased cell proliferation and decreased apoptosis. Single-cell RNA sequencing and real-time impedance measurements support increased cytotoxicity of mutated CD4 T cells. High throughput drug-sensitivity testing suggests that mutations induce resistance to mTOR inhibitors, but increase sensitivity for HSP90 inhibitors. Our findings imply that somatic mutations may contribute to aberrant T cell proliferations and persistent immune activation in cGvHD, thereby paving the way for targeted therapies.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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