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Journal articles
Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma
Fabrice Jardin
1, *
A. Pujals
2
L. Pelletier
2
E. Bohers
1
V. Camus
1
S. Mareschal
1
S. Dubois
1
Brigitte Sola
3
Marlène Ochmann
4
F. Lemonnier
2
P.-J. Viailly
1
P. Bertrand
1
C. Maingonnat
1
Alexandra Traverse-Glehen
4
P. Gaulard
2
D. Damotte
5
R. Delarue
5
C. Haioun
2
C. Argueta
6
Y. Landesman
6
G. Salles
7
J.-P. Jais
6
M. Figeac
8
C. Copie-Bergman
9
T.J. Molina
10
J.M. Picquenot
1
M. Cornic
1
Thierry Fest
4
N. Milpied
11
E. Lemasle
1
A. Stamatoullas
1
P. Moeller
12
M.J.S. Dyer
13
C. Sundstrom
14
C. Bastard
1
H. Tilly
15
K. Leroy
2
*
Corresponding author
V. Camus 1
Author
S. Mareschal 1
Author
S. Dubois 1
Author
Brigitte Sola 3
Author IdHAL : brigitte-sola ORCID : https://orcid.org/0000-0001-7278-9651
K. Leroy 2
Author
1
GPL - Groupe d'étude des proliférations lymphoïdes (Centre Henri Becquerel 1, rue d'Amiens 76038 Rouen cedex - France)
- UNIROUEN - Université de Rouen Normandie (1, rue Thomas Becket 76821 Mont-Saint-Aignan Cedex - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U918 (101, rue de Tolbiac, 75013 Paris - France)
2
Service d'hématologie clinique (Créteil - France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
- Hôpital Henri Mondor (France)
- UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12 (61 avenue du Général de Gaulle - 94010 Créteil cedex - France)
3
MILPAT - Microenvironnement cellulaire et pathologie (UFR Médecine, CHU, avenue Côte de Nacre, 14033 Caen cedex 9 - France)
- UNICAEN - Université de Caen Normandie : EA 4652 (Esplanade de la Paix - CS 14032 - 14032 CAEN Cedex 5 - France)
- NU - Normandie Université (Esplanade de la Paix - CS 14032 - 14032 Caen Cedex 5 - France)
4
MiCa - Microenvironnement et cancer (INSERM UMR917, Campus Santé, Bât 2, Université de Rennes 1, 2 Avenue du Professeur Léon Bernard, 35043 Rennes, France - France)
- UR1 - Université de Rennes 1 (2 rue du Thabor - CS 46510 - 35065 Rennes cedex - France)
- UNIV-RENNES - Université de Rennes (France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U917 (101, rue de Tolbiac, 75013 Paris - France)
- Biosit : Biologie - Santé - Innovation Technologique - Structure Fédérative de Recherche en Biologie et Santé de Rennes (Université Rennes 1 - Campus Santé Villejean - 2, avenue Professeur Léon Bernard 35043 Rennes cedex - France)
5
CRC (UMR_S 872) - Centre de Recherche des Cordeliers (CRBM des Cordeliers 15, rue de l'ecole de medecine batiment E 75270 Paris cedex 06 - France)
- UPD5 - Université Paris Descartes - Paris 5 : U872 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
- UPMC - Université Pierre et Marie Curie - Paris 6 (4 place Jussieu - 75005 Paris - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U872 (101, rue de Tolbiac, 75013 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : UMR 872 (France)
6
CHU Necker - Enfants Malades [AP-HP] (149 Rue de Sèvres 75015 Paris - France)
7
Service d'hématologie [Hôpital Edouard Herriot - HCL] (5, place d'Arsonval - 69437 LYON cedex 03 - France)
- Hôpital Edouard Herriot [CHU - HCL] (5 Place d'Arsonval
69003 Lyon - France)
- HCL - Hospices Civils de Lyon (3 Quai des Célestins 69002 Lyon - France)
9
IMRB - Institut Mondor de Recherche Biomédicale (8 rue du Général Sarrail 94010 Créteil - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U955 (101, rue de Tolbiac, 75013 Paris - France)
- UPEC UP12 - Université Paris-Est Créteil Val-de-Marne - Paris 12 : UMR955 (61 avenue du Général de Gaulle - 94010 Créteil cedex - France)
- IFR10 (France)
10
UPD5 - Université Paris Descartes - Paris 5 (12, rue de l'École de Médecine - 75270 Paris cedex 06 - France)
11
CHU Nantes - Centre hospitalier universitaire de Nantes (1 Place Alexis-Ricordeau, 44000 Nantes - France)
12
Institute of Human Genetics, University of Ulm (Albert-Einstein-Allee 11, Ulm, Germany - Germany)
13
University of Leicester (University Rd, Leicester LE1 7RH - United Kingdom)
15
Service hématologie Poitiers (Poitiers - France)
- CHU Poitiers - Centre hospitalier universitaire de Poitiers (2 Rue de la Milétrie, 86021 Poitiers - France)
Abstract : Primary mediastinal B-cell lymphoma (PMBL) is an entity of B-cell lymphoma distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We investigated the prevalence, specificity, and clinical relevance of mutations of XPO1, which encodes a member of the karyopherin-β nuclear transporters, in a large cohort of PMBL. PMBL cases defined histologically or by gene expression profiling (GEP) were sequenced and the XPO1 mutational status was correlated to genetic and clinical characteristics. The XPO1 mutational status was also assessed in DLBCL, Hodgkin lymphoma (HL) and mediastinal gray-zone lymphoma (MGZL).The biological impact of the mutation on Selective Inhibitor of Nuclear Export (SINE) compounds (KPT-185/330) sensitivity was investigated in vitro. XPO1 mutations were present in 28/117 (24%) PMBL cases and in 5/19 (26%) HL cases but absent/rare in MGZL (0/20) or DLBCL (3/197). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in GEP-defined PMBL and was associated with shorter PFS. Age, International Prognostic Index and bulky mass were similar in XPO1 mutant and wild-type cases. KPT-185 induced a dose-dependent decrease in cell proliferation and increased cell-death in PMBL cell lines harboring wild type or XPO1 E571K mutant alleles. Experiments in transfected U2OS cells further confirmed that the XPO1 E571K mutation does not have a drastic impact on KPT-330 binding. To conclude the XPO1 E571K mutation represents a genetic hallmark of the PMBL subtype and serves as a new relevant PMBL biomarker. SINE compounds appear active for both mutated and wild-type protein.
Document type :
Journal articles
Complete list of metadatas
https://hal-univ-rennes1.archives-ouvertes.fr/hal-01372756
Contributor : Xavier Chard-Hutchinson <>
Submitted on : Friday, November 4, 2016 - 4:27:30 PM
Last modification on : Thursday, January 14, 2021 - 11:29:08 AM
Contributor : Xavier Chard-Hutchinson <>
Submitted on : Friday, November 4, 2016 - 4:27:30 PM
Last modification on : Thursday, January 14, 2021 - 11:29:08 AM
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Recurrent mutations of the exp...
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Identifiers
- HAL Id : hal-01372756, version 1
- DOI : 10.1002/ajh.24451
- PUBMED : 27312795
Collections
HCL | UPMC | HEH | IMRB | UPEC-UPEM | UNIV-RENNES1 | UNIV-PARIS5 | U917 | COMUE-NORMANDIE | BIOSIT | CORDELIERS | UR1-UFR-SVE | USPC | CALYM | MICMAC | UNIV-RENNES | UNIROUEN | UNICAEN | CNRS | SORBONNE-UNIVERSITE | SU-SCIENCES | UPEC | UNIV-PARIS | GPMCND | SU-TI
Citation
Fabrice Jardin, A. Pujals, L. Pelletier, E. Bohers, V. Camus, et al.. Recurrent mutations of the exportin 1 gene (XPO1) and their impact on selective inhibitor of nuclear export compounds sensitivity in primary mediastinal B-cell lymphoma. American Journal of Hematology, Wiley, 2016, 91 (9), pp.923-930. ⟨10.1002/ajh.24451⟩. ⟨hal-01372756⟩
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