Germline HAVCR2 mutations altering TIM-3 characterize subcutaneous panniculitis-like T cell lymphomas with hemophagocytic lymphohistiocytic syndrome PMID: 30374066

ADC Targets in Oncology

2026-04-10

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

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. [email protected].
30. Centre d'Etudes des Déficits Immunitaires, Centre Hospitalier Universitaire Paris, Hôpital Necker-Enfants Malades, Paris, France. [email protected].
31. Department of Human Genetics, McGill University, Montreal, Quebec, Canada. [email protected].
32. Department of Pediatrics, McGill University, Montreal, Quebec, Canada. [email protected].
33. Research Institute, McGill University Health Centre, Montreal, Quebec, Canada. [email protected].
# Contributed equally.

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 survival^1,2. 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.