Title :

Oncogenetic landscape of lymphomagenesis in coeliac disease

Author(s) :

Cording, Sascha [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Lhermitte, Ludovic [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Malamut, Georgia [Auteur]
Hôpital Cochin [AP-HP]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Berrabah, Sofia [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Trinquand, Amelie [Auteur]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Guegan, Nicolas [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Villarese, Patrick [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Kaltenbach, Sophie [Auteur]
Laboratoire Histologie Embryologie Cytogénétique [CHU Necker]
Meresse, Bertrand [Auteur]
Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286
Khater, Sherine [Auteur]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Dussiot, Michael [Auteur]
Imagine - Institut des maladies génétiques [IMAGINE - U1163]
Bras, Marc [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Cheminant, Morgane [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Tesson, Bruno [Auteur]
Institut Carnot Lymphome [CALYM]
Bole-Feysot, Christine [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Bruneau, Julie [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Molina, Thierry Jo [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications [ERL 8254]
Sibon, David [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Macintyre, Elizabeth [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Hermine, Olivier [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]
Mécanismes cellulaires et moléculaires des désordres hématologiques et implications thérapeutiques = Molecular mechanisms of hematological disorders and therapeutic implications [ERL 8254]
Cellier, Christophe [Auteur]
Hôpital Européen Georges Pompidou [APHP] [HEGP]
Asnafi, Vahid [Auteur]
Hôpital Necker - Enfants Malades [AP-HP]
Institut Necker Enfants-Malades [INEM - UM 111 (UMR 8253 / U1151)]
Cerf-Bensussan, Nadine [Auteur]
Imagine - Institut des maladies génétiques (IHU) [Imagine - U1163]

Journal title :

Gut

Abbreviated title :

Gut

Publication date :

2021-02-12

ISSN :

1468-3288

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

OBJECTIVE: 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 ...
Show more >OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.Show less >

Language :

Anglais

Peer reviewed article :

Oui

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Institut de Recherche Translationnelle sur l'Inflammation (INFINITE) - U1286

Submission date :

2021-07-06T12:44:42Z
2024-03-01T16:10:30Z
2024-03-01T16:12:17Z