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

Daehong Kim, Giljun Park, Jani Huuhtanen, Sofie Lundgren, Rajiv K. Khajuria, Ana M. Hurtado, Cecilia Muñoz-Calleja, Laura Cardeñoso, Valle Gómez-García de Soria, Tzu Hua Chen-Liang, Samuli Eldfors, Pekka Ellonen, Sari Hannula, Matti Kankainen, Oscar Bruck, Anna Kreutzman, Urpu Salmenniemi, Tapio Lönnberg, Andrés Jerez, Maija Itälä-Remes, Mikko Myllymäki, Mikko A. I. Keränen and Satu Mustjoki ()
Additional contact information
Daehong Kim: Helsinki University Hospital Comprehensive Cancer Center
Giljun Park: Helsinki University Hospital Comprehensive Cancer Center
Jani Huuhtanen: Helsinki University Hospital Comprehensive Cancer Center
Sofie Lundgren: Helsinki University Hospital Comprehensive Cancer Center
Rajiv K. Khajuria: Helsinki University Hospital Comprehensive Cancer Center
Ana M. Hurtado: Universidad de Murcia, IMIB
Cecilia Muñoz-Calleja: Instituto de Investigación Sanitaria Princesa
Laura Cardeñoso: Instituto de Investigación Sanitaria Princesa
Valle Gómez-García de Soria: Instituto de Investigación Sanitaria Princesa
Tzu Hua Chen-Liang: Universidad de Murcia, IMIB
Samuli Eldfors: University of Helsinki
Pekka Ellonen: University of Helsinki
Sari Hannula: University of Helsinki
Matti Kankainen: Helsinki University Hospital Comprehensive Cancer Center
Oscar Bruck: Helsinki University Hospital Comprehensive Cancer Center
Anna Kreutzman: Helsinki University Hospital Comprehensive Cancer Center
Urpu Salmenniemi: Turku University Hospital
Tapio Lönnberg: University of Turku and Åbo Akademi University
Andrés Jerez: Universidad de Murcia, IMIB
Maija Itälä-Remes: Turku University Hospital
Mikko Myllymäki: Helsinki University Hospital Comprehensive Cancer Center
Mikko A. I. Keränen: Helsinki University Hospital Comprehensive Cancer Center
Satu Mustjoki: Helsinki University Hospital Comprehensive Cancer Center

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: 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.

Date: 2020
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-16115-w

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DOI: 10.1038/s41467-020-16115-w

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