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

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ID: 12444
2018
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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. 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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gayden2018germlinenature Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Tenzin Gayden, Fernando E Sepulveda, Dong-Anh Khuong-Quang, Jonathan Pratt, Elvis T Valera, Alexandrine Garrigue, Susan Kelso, Frank Sicheri, Leonie G Mikael, Nancy Hamel, Andrea Bajic, Rola Dali, Shriya Deshmukh, Dzana Dervovic, Daniel Schramek, Frédéric Guerin, Mikko Taipale, Hamid Nikbakht, Jacek Majewski, Despina Moshous, Janie Charlebois, Sharon Abish, Christine Bole-Feysot, Patrick Nitschke, Brigitte Bader-Meunier, David Mitchell, Catherine Thieblemont, Maxime Battistella, Simon Gravel, Van-Hung Nguyen, Rachel Conyers, Jean-Sebastien Diana, Chris McCormack, H Miles Prince, Marianne Besnard, Stephane Blanche, Paul G Ekert, Sylvie Fraitag, William D Foulkes, Alain Fischer, Bénédicte Neven, David Michonneau, Geneviève de Saint Basile, Nada Jabado
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Journal nature genetics
Year 2018
DOI
10.1038/s41588-018-0251-4
URL
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