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Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease.

Daehong KimGiljun ParkJani HuuhtanenSofie LundgrenRajiv K KhajuriaAna María Hurtado LópezCecilia Muñoz-CallejaLaura CardeñosoValle Gómez-García de SoriaTzu Hua Chen-LiangSamuli EldforsPekka EllonenSari HannulaMatti KankainenOscar BrückAnna KreutzmanUrpu SalmenniemiTapio LönnbergAndrés JerezMaija Itälä-RemesMikko MyllymäkiMikko A I KeränenMohamed El Missiry
Published in: Nature communications (2020)
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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