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

Author(s):Show less -

Gayden, Tenzin ^[1] ; Sepulveda, Fernando E. ^{[2, 3]} ; Khuong-Quang, Dong-Anh ; Pratt, Jonathan ^[1] ; Valera, Elvis T. ^{[4, 1]} ; Garrigue, Alexandrine ^{[2, 3]} ; Kelso, Susan ^{[5, 6]} ; Sicheri, Frank ^{[5, 6]} ; Mikael, Leonie G. ^[1] ; Hamel, Nancy ^[7] ; Bajic, Andrea ^[1] ; Dali, Rola ^[8] ; Deshmukh, Shriya ^[9] ; Dervovic, Dzana ^[6] ; Schramek, Daniel ^{[5, 6]} ; Guerin, Frederic ^{[2, 3]} ; Taipale, Mikko ^[5] ; Nikbakht, Hamid ^{[1, 8]} ; Majewski, Jacek ^{[1, 10, 11]} ; Moshous, Despina ^[12] ; Charlebois, Janie ^[13] ; Abish, Sharon ^[13] ; Bole-Feysot, Christine ^[14] ; Nitschke, Patrick ^[15] ; Bader-Meunier, Brigitte ^[12] ; Mitchell, David ^[13] ; Thieblemont, Catherine ^{[16, 17]} ; Battistella, Maxime ^{[16, 18]} ; Gravel, Simon ^{[10, 11]} ; Nguyen, Van-Hung ; Conyers, Rachel ^{[19, 20, 21]} ; Diana, Jean-Sebastien ^[12] ; McCormack, Chris ^{[22, 23]} ; Prince, H. Miles ^{[24, 25, 26]} ; Besnard, Marianne ^[27] ; Blanche, Stephane ^[12] ; Ekert, Paul G. ^{[19, 20, 21]} ; Fraitag, Sylvie ^[28] ; Foulkes, William D. ^{[1, 7]} ; Fischer, Alain ^{[2, 12, 29, 30]} ; Neven, Benedicte ^{[2, 12, 30]} ; Michonneau, David ^{[16, 31]} ; de Saint Basile, Genevieve ^{[2, 3, 32]} ; Jabado, Nada ^{[1, 33, 34]}

Affiliation:Show less -

^[1] McGill Univ, Dept Human Genet, Montreal, PQ - Canada

^[2] Univ Paris 05, Sorbonne Paris Cite, Paris - France

^[3] Inst Imagine, Lab Normal & Pathol Homeostasis Immune Syst, INSERM, U1163, Paris - France

^[4] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pediat, Sao Paulo - Brazil

^[5] Univ Toronto, Dept Mol Genet, Toronto, ON - Canada

^[6] Sinai Hlth Syst, Lunenfeld Tanenbaum Res Inst, Toronto, ON - Canada

^[7] McGill Univ, Ctr Hlth, Res Inst, Canc Res Program, Montreal, PQ - Canada

^[8] Canadian Ctr Computat Genom, Montreal, PQ - Canada

^[9] McGill Univ, Dept Expt Med, Montreal, PQ - Canada

^[10] McGill Univ, Montreal, PQ - Canada

^[11] Genome Quebec Innovat Ctr, Montreal, PQ - Canada

^[12] Hop Necker Enfants Malad, AP HP, Dept Pediat Immunol & Hematol, Paris - France

^[13] McGill Univ, Ctr Hlth, Montreal Childrens Hosp, Div Hematol & Oncol, Montreal, PQ - Canada

^[14] Inst Imagine, Plateforme Genom, Paris - France

^[15] Univ Sorbonne Paris Cite, Univ Paris Descartes, Plateforme Bioinformat, Paris - France

^[16] Univ Sorbonne Paris Cite, Paris Diderot Univ, Paris - France

^[17] St Louis Hosp, Hematol & Oncol Unit, Paris - France

^[18] St Louis Hosp, Cytol & Pathol Lab, Paris - France

^[19] Dong-Anh Khuong-Quang, Royal Childrens Hosp, Childrens Canc Ctr, Parkville, Vic - Australia

^[20] Dong-Anh Khuong-Quang, Murdoch Childrens Res Inst, Parkville, Vic - Australia

^[21] Dong-Anh Khuong-Quang, Univ Melbourne, Dept Pediat, Parkville, Vic - Australia

^[22] Univ Melbourne, Peter MacCallum Canc Inst, Dept Surg Oncol, Melbourne, Vic - Australia

^[23] St Vincents Hosp, Dept Dermatol, Fitzroy, Vic - Australia

^[24] Univ Melbourne, Melbourne, Vic - Australia

^[25] Epworth Healthcare, Melbourne, Vic - Australia

^[26] Sir Peter MacCallum Canc Ctr, Dept Med Oncol, Melbourne, Vic - Australia

^[27] Ctr Hosp Polynesie Francaise, Dept Neonatol, Papeete, French Polynesi - Fr Polynesia

^[28] CHU Paris, Hop Necker Enfants Malad, Dept Anat & Cytol Pathol, Paris - France

^[29] Coll France, Paris - France

^[30] Inst Imagine, INSERM, U1163, Paris - France

^[31] St Louis Hosp, Hematol & Transplantat Unit, Paris - France

^[32] CHU Paris, Hop Necker Enfants Malad, Ctr Etud Deficits Immunitaires, Paris - France

^[33] McGill Univ, Dept Pediat, Montreal, PQ - Canada

^[34] McGill Univ, Ctr Hlth, Res Inst, Montreal, PQ - Canada

• Document type: Journal article
• Source: Nature Genetics; v. 50, n. 12, p. 1650+, DEC 2018.
• Web of Science Citations: 9

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 similar to 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-alpha and interleukin-1 beta, 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. (AU)

• FAPESP's process: 15/20142-0 - Dynamic plasmatic detection of the H3.3 mutation status in patients with high-grade astrocytomas (HGA)
• Grantee: Elvis Terci Valera
• Support Opportunities: Scholarships abroad - Research