한빛사논문
Daehong Kim1,2,13, Giljun Park1,2,13, Jani Huuhtanen1,2, Sofie Lundgren1,2, Rajiv K. Khajuria1, Ana M. Hurtado3, Cecilia Muñoz-Calleja4, Laura Cardeñoso5, Valle Gómez-García de Soria6, Tzu Hua Chen-Liang3, Samuli Eldfors7, Pekka Ellonen7, Sari Hannula7, Matti Kankainen1,2,8,9, Oscar Bruck1,2,9, Anna Kreutzman1,2, Urpu Salmenniemi10, Tapio Lönnberg11, Andrés Jerez3, Maija Itälä-Remes10, Mikko Myllymäki1,2, Mikko A. I. Keränen1,2,12 & Satu Mustjoki1,2,9,*
1Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, 00290 Helsinki, Finland.
2Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, 00014 Helsinki, Finland.
3Hematology and Medical Oncology Department, Hospital Morales Meseguer. Centro Regional de Hemodonación, Universidad de Murcia, IMIB, 30008 Murcia, Spain.
4Department of Immunology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain.
5Department of Microbiology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain.
6Department of Hematology, Hospital Universitario de La Princesa, Instituto de Investigación Sanitaria Princesa, 28006 Madrid, Spain.
7Institute of Molecular Medicine Finland (FIMM), University of Helsinki, 00014 Helsinki, Finland.
8Department of Medical and Clinical Genetics, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.
9iCAN Digital Precision Cancer Medicine, University of Helsinki and Helsinki University Hospital, 00014 Helsinki, Finland.
10Stem Cell transplantation unit, Turku University Hospital, 20521 Turku, Finland.
11Turku Bioscience Centre, University of Turku and Åbo Akademi University, 20520 Turku, Finland.
12Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, 00029 Helsinki, Finland.
13These authors contributed equally: Daehong Kim, Giljun Park.
*Corresponding author
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.
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