Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease
Laura Cardeñoso; Sari Hannula; Valle Gómez-García de Soria; Mikko A. I. Keränen; Rajiv K. Khajuria; Tzu Hua Chen-Liang; Cecilia Muñoz-Calleja; Tapio Lönnberg; Anna Kreutzman; Sofie Lundgren; Ana M. Hurtado; Oscar Bruck; Mikko Myllymäki; Andrés Jerez; Jani Huuhtanen; Samuli Eldfors; Maija Itälä-Remes; Satu Mustjoki; Urpu Salmenniemi; Daehong Kim; Matti Kankainen; Giljun Park; Pekka Ellonen
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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