2. Academic Validation
  3. Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome

  • Nat Genet. 2018 Dec;50(12):1650-1657. doi: 10.1038/s41588-018-0251-4.
Tenzin Gayden # 1,  Fernando E Sepulveda # 2,  Dong-Anh Khuong-Quang # 3 4,  Jonathan Pratt # 1,  Elvis T Valera 1 5,  Alexandrine Garrigue 2,  Susan Kelso 6 7,  Frank Sicheri 6 7,  Leonie G Mikael 1,  Nancy Hamel 8,  Andrea Bajic 1,  Rola Dali 9,  Shriya Deshmukh 10,  Dzana Dervovic 6,  Daniel Schramek 6 7,  Frédéric Guerin 2,  Mikko Taipale 7,  Hamid Nikbakht 1 9,  Jacek Majewski 1 11,  Despina Moshous 12,  Janie Charlebois 13,  Sharon Abish 13,  Christine Bole-Feysot 14,  Patrick Nitschke 15,  Brigitte Bader-Meunier 12,  David Mitchell 13,  Catherine Thieblemont 16 17,  Maxime Battistella 17 18,  Simon Gravel 11,  Van-Hung Nguyen 19,  Rachel Conyers 3 4,  Jean-Sebastien Diana 12,  Chris McCormack 20 21,  H Miles Prince 22 23,  Marianne Besnard 24,  Stephane Blanche 12,  Paul G Ekert 3 4,  Sylvie Fraitag 25,  William D Foulkes 1 8,  Alain Fischer 12 26 27,  Bénédicte Neven 12 27,  David Michonneau 17 28,  Geneviève de Saint Basile 29 30,  Nada Jabado 31 32 33
Affiliations

Affiliations

  • 1 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
  • 2 Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM U1163, Institut Imagine, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France.
  • 3 Children's Cancer Center, The Royal Children's Hospital and Murdoch Children's Research Institute, Parkville, Victoria, Australia.
  • 4 Department of Pediatrics, University of Melbourne, Parkville, Victoria, Australia.
  • 5 Department of Pediatrics, Ribeirão Preto Medical School, University of São Paulo, São Paulo, Brazil.
  • 6 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
  • 7 Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
  • 8 Cancer Research Program, Research Institute of the McGill University Health Center, Montreal, Quebec, Canada.
  • 9 Canadian Centre for Computational Genomics, Montreal, Quebec, Canada.
  • 10 Department of Experimental Medicine, McGill University, Montreal, Quebec, Canada.
  • 11 McGill University and Genome Quebec Innovation Center, Montreal, Quebec, Canada.
  • 12 Department of Pediatric Immunology and Hematology, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
  • 13 Division of Hematology and Oncology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • 14 Plateforme de Génomique, Institut Imagine, Paris, France.
  • 15 Plateforme de Bioinformatique, Université Paris Descartes, Université Sorbonne Paris Cité, Paris, France.
  • 16 Hematology and Oncology Unit, Saint Louis Hospital, Paris, France.
  • 17 Paris Diderot University, Université Sorbonne Paris Cité, Paris, France.
  • 18 Cytology and Pathology Laboratory, Saint Louis Hospital, Paris, France.
  • 19 Department of Pathology, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
  • 20 Department of Surgical Oncology, Peter MacCallum Cancer Institute, University of Melbourne, Melbourne, Victoria, Australia.
  • 21 Department of Dermatology, St. Vincent's Hospital, Fitzroy, Victoria, Australia.
  • 22 Epworth Healthcare, Melbourne, Victoria, Australia.
  • 23 Department of Medical Oncology, Sir Peter MacCallum Cancer Centre and University of Melbourne, Melbourne, Victoria, Australia.
  • 24 Department of Neonatology, Centre Hospitalier de Polynésie Française, Papeete, French Polynesia.
  • 25 Department of Anatomy and Cytology/Pathology, Centre Hospitalier Universitaire Paris, Hôpital Necker-Enfants Malades, Paris, France.
  • 26 Collège de France, Paris, France.
  • 27 INSERM U1163, Institut Imagine and Université Paris Descartes -Sorbonne Paris Cité, Paris, France.
  • 28 Hematology and Transplantation Unit, Saint Louis Hospital, Paris, France.
  • 29 Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM U1163, Institut Imagine, and Université Paris Descartes-Sorbonne Paris Cité, Paris, France. genevieve.de-saint-basile@inserm.fr.
  • 30 Centre d'Etudes des Déficits Immunitaires, Centre Hospitalier Universitaire Paris, Hôpital Necker-Enfants Malades, Paris, France. genevieve.de-saint-basile@inserm.fr.
  • 31 Department of Human Genetics, McGill University, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
  • 32 Department of Pediatrics, McGill University, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
  • 33 Research Institute, McGill University Health Centre, Montreal, Quebec, Canada. nada.jabado@mcgill.ca.
  • # Contributed equally.
PMID: 30374066 DOI: 10.1038/s41588-018-0251-4
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.

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