Please use this identifier to cite or link to this item: http://hdl.handle.net/11434/1569
Title: Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome.
Authors: Prince, Miles
Other Authors: Gayden, Tenzin
Sepulveda, Fernando
Khuong-Quang, Dong-Anh
Pratt, Jonathan
Valera, Elvis
Garrigue, Alexandrine
Kelso, Susan
Sicheri, Frank
Mikael, Leonie
Hamel, Nancy
Bajic, Andrea
Dali, Rola
Deshmukh, Shriya
Dervovic, Dzana
Schramek, Daniel
Guerin, Frederic
Taipale, Mikko
Nikbakht, Hamid
Majewski, Jacek
Moshous, Despina
Charlebois, Janie
Abish, Sharon
Bole-Feysot, Christine
Nitschke, Patrick
Bader-Meunier, Brigitte
Mitchell, David
Thieblemont, Catherine
Battistella, Maxime
Gravel, Simon
Nguyen, Van-Hung
Conyers, Rachel
Diana, Jean-Sebastien
McCormack, Chris
Besnard, Marianne
Blanche, Stephane
Ekert, Paul
Fraitag, Sylvie
Foulkes, William
Fischer, Alain
Neven, Benedicte
Michonneau, David
de Saint Basile, Genevieve
Jabado, Nada
Keywords: Subcutaneous Panniculitis-Like T Cell Lymphoma
SPTCL
Non-Hodgkin Lymphoma
Hemophagocytic Lymphohistiocytosis
HLH
Immune Activation
T Cell Immunoglobulin Mucin 3
TIM-3
Immune Responses
Immune Cells
Gene Mutations
Inflammatory Cytokines
Immunomodulation
Therapeutic Repression
Issue Date: Oct-2018
Publisher: Nature Publishing Group
Citation: Nat Genet. 2018 Oct 29
Abstract: Subcutaneous panniculitis-like T cell lymphoma (SPTCL), a non-Hodgkin lymphoma, can be associated with hemophagocytic lymphohistiocytosis (HLH), a life-threatening immune activation that adversely affects survival1,2. T cell immunoglobulin mucin 3 (TIM-3) is a modulator of immune responses expressed on subgroups of T and innate immune cells. We identify in ~60% of SPTCL cases germline, loss-of-function, missense variants altering highly conserved residues of TIM-3, c.245A>G (p.Tyr82Cys) and c.291A>G (p.Ile97Met), each with specific geographic distribution. The variant encoding p.Tyr82Cys TIM-3 occurs on a potential founder chromosome in patients with East Asian and Polynesian ancestry, while p.Ile97Met TIM-3 occurs in patients with European ancestry. Both variants induce protein misfolding and abrogate TIM-3's plasma membrane expression, leading to persistent immune activation and increased production of inflammatory cytokines, including tumor necrosis factor-α and interleukin-1β, promoting HLH and SPTCL. Our findings highlight HLH-SPTCL as a new genetic entity and identify mutations causing TIM-3 alterations as a causative genetic defect in SPTCL. While HLH-SPTCL patients with mutant TIM-3 benefit from immunomodulation, therapeutic repression of the TIM-3 checkpoint may have adverse consequences.
URI: http://hdl.handle.net/11434/1569
DOI: 10.1038/s41588-018-0251-4
PubMed URL: https://www.ncbi.nlm.nih.gov/pubmed/30374066
ISSN: 1061-4036
1546-1718
Journal Title: Nature Genetics
Type: Journal Article
Affiliated Organisations: Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM U1163, Institut Imagine, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
Children's Cancer Center, The Royal Children's Hospital and Murdoch Children's Research Institute, Parkville, Victoria, Australia
Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia.
Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
Department of Pediatric Immunology and Hematology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
Division of Hematology and Oncology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Plateforme de Génomique, Institut Imagine, Paris, France.
Plateforme de Bioinformatique, Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France.
Hematology and Oncology Unit, Saint Louis Hospital, Paris, France.
Paris Diderot University, Université Sorbonne Paris Cité, Paris, France.
Cytology and Pathology Laboratory, Saint Louis Hospital, Paris, France.
Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Department of Surgical Oncology, Peter MacCallum Cancer Institute, University of Melbourne, Melbourne, Victoria, Australia.
Department of Dermatology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
Department of Medical Oncology, Sir Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.
Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia.
Department of Anatomy and Cytology/Pathology, Centre Hospitalier Universitaire Paris, Hôpital Necker-Enfants Malades, Paris, France.
Collège de France, Paris, France.
INSERM U1163, Institut Imagine and Université Paris Descartes -Sorbonne Paris Cité, Paris, France.
Hematology and Transplantation Unit, Saint Louis Hospital, Paris, France.
Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM U1163, Institut Imagine, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France
Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
Department of Pediatrics, McGill University, Montreal, Quebec, Canada.
Research Institute, McGill University Health Centre, Montreal, Quebec, Canada.
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