Somatic mTOR mutation in clonally expanded T lymphocytes associated with chronic graft versus host disease.
Nat Commun
; 11(1): 2246, 2020 05 07.
Article
em En
| MEDLINE
| ID: mdl-32382059
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Linfócitos T
/
Serina-Treonina Quinases TOR
/
Doença Enxerto-Hospedeiro
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Nat Commun
Ano de publicação:
2020
Tipo de documento:
Article