Advanced search
Start date
Betweenand
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
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]
Total Authors: 44
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
Total Affiliations: 34
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