Oncogenetic landscape of lymphomagenesis in coeliac disease.
Adult
Aged
Aged, 80 and over
Celiac Disease
/ complications
Cohort Studies
Enteropathy-Associated T-Cell Lymphoma
/ etiology
Female
France
Gain of Function Mutation
/ genetics
Humans
Janus Kinase 1
/ genetics
Lymphocytes
/ physiology
Male
Middle Aged
STAT3 Transcription Factor
/ genetics
Young Adult
COELIAC DISEASE
GASTROINTESTINAL LYMPHOMA
GENE MUTATION
Journal
Gut
ISSN: 1468-3288
Titre abrégé: Gut
Pays: England
ID NLM: 2985108R
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
received:
31
08
2020
revised:
26
01
2021
accepted:
27
01
2021
pubmed:
14
2
2021
medline:
9
3
2022
entrez:
13
2
2021
Statut:
ppublish
Résumé
Enteropathy-associated T-cell lymphoma (EATL) is a rare but severe complication of coeliac disease (CeD), often preceded by low-grade clonal intraepithelial lymphoproliferation, referred to as type II refractory CeD (RCDII). Knowledge on underlying oncogenic mechanisms remains scarce. Here, we analysed and compared the mutational landscape of RCDII and EATL in order to identify genetic drivers of CeD-associated lymphomagenesis. Pure populations of RCDII-cells derived from intestinal biopsies (n=9) or sorted from blood (n=2) were analysed by whole exome sequencing, comparative genomic hybridisation and RNA sequencing. Biopsies from RCDII (n=50), EATL (n=19), type I refractory CeD (n=7) and uncomplicated CeD (n=18) were analysed by targeted next-generation sequencing. Moreover, functional in vitro studies and drug testing were performed in RCDII-derived cell lines. 80% of RCDII and 90% of EATL displayed somatic gain-of-functions mutations in the JAK1-STAT3 pathway, including a remarkable p.G1097 hotspot mutation in the JAK1 kinase domain in approximately 50% of cases. Other recurrent somatic events were deleterious mutations in nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB) regulators TNFAIP3 and TNIP3 and potentially oncogenic mutations in TET2, KMT2D and DDX3X. JAK1 inhibitors, and the proteasome inhibitor bortezomib could block survival and proliferation of malignant RCDII-cell lines. Mutations activating the JAK1-STAT3 pathway appear to be the main drivers of CeD-associated lymphomagenesis. In concert with mutations in negative regulators of NF-κB, they may favour the clonal emergence of malignant lymphocytes in the cytokine-rich coeliac intestine. The identified mutations are attractive therapeutic targets to treat RCDII and block progression towards EATL.
Identifiants
pubmed: 33579790
pii: gutjnl-2020-322935
doi: 10.1136/gutjnl-2020-322935
pmc: PMC8862029
doi:
Substances chimiques
STAT3 Transcription Factor
0
STAT3 protein, human
0
JAK1 protein, human
EC 2.7.10.2
Janus Kinase 1
EC 2.7.10.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
497-508Investigateurs
Yoram Bouhnik
(Y)
Charles-André Cuenod
(CA)
Sabine Brechignac
(S)
Matthieu Allez
(M)
Jacques Cosnes
(J)
Agnès Fourmestraux
(A)
Jean-Charles Delchier
(JC)
Jehan Dupuis
(J)
Corinne Haioun
(C)
Taoufik El Gnaoui
(TE)
Eric Lerebours
(E)
Guillaume Savoye
(G)
Herve Tilly
(H)
Bernard Flourie
(B)
Bertrand Coiffier
(B)
Xavier Hebuterne
(X)
Nadia Arab
(N)
Jérôme Filippi
(J)
Stéphane Schneider
(S)
Frank Zerbib
(F)
Noel Milpied
(N)
Krimo Bouabdallah
(K)
Reza Tabrizi
(R)
Stéphane Vigouroux
(S)
Arnaud Pigneux
(A)
Thibaut Leguay
(T)
Marie-Sarah Dilhuydy
(MS)
Charles Dauriac
(C)
Serge Bologna
(S)
Cyrille Hulin
(C)
Caroline Bonmati
(C)
Fréderic Magnin
(F)
Dana Ranta
(D)
Tamara Matysiakbudnik
(T)
Eric Deconinck
(E)
Philippe Pouderoux
(P)
Bruno Bonaz
(B)
Remy Gressin
(R)
Franck Carbonnel
(F)
Jean-Marc Gornet
(JM)
Julien Branche
(J)
Georgette Saint-Georges
(G)
Jean-Marie Reimund
(JM)
Stéphane Nancey
(S)
Maria Nachury
(M)
Stéphanie Viennot
(S)
Camille Zallot
(C)
Bettina Fabiani
(B)
Lysiane Marthey
(L)
Karine Juvin
(K)
Yann Le Baleur
(YL)
Sandy Kwiatek
(S)
Eric Saillard
(E)
Dominique Louvel
(D)
Xavier Roblin
(X)
Philippe Beau
(P)
Pierre Feugier
(P)
Laurent Peyrin-Biroulet
(L)
Hélène Zanaldi
(H)
Hedia Brixi-Benmansour
(H)
Guillaume Cadiot
(G)
Thierry Lecomte
(T)
Jean-Francois Bretagne
(JF)
Olivier Casasnovas
(O)
Denis Caillot
(D)
Laurent Bedenne
(L)
Jacques-Olivier Bay
(JO)
Corinne Bouteloup
(C)
Bernard Duclos
(B)
Carine Foucaud
(C)
Informations de copyright
© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.
Déclaration de conflit d'intérêts
Competing interests: None declared.
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