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.
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. Am. J. Hematol. 91:923-930, 2016. © 2016 Wiley Periodicals, Inc.
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Fabrice
F
Jardin
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Anais
A
Pujals
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Laura
L
Pelletier
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Elodie
E
Bohers
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Vincent
V
Camus
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Sylvain
S
Mareschal
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Sydney
S
Dubois
Departement of Hematology, Normandie Univ, UNICAEN, Caen, EA4652, France.
Brigitte
B
Sola
Departement of Hematology, Inserm U917, CHU Pontchaillou, Rennes, France.
Marlène
M
Ochmann
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
François
F
Lemonnier
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Pierre-Julien
PJ
Viailly
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Philippe
P
Bertrand
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Catherine
C
Maingonnat
Departement of Hematology, Inserm U917, CHU Pontchaillou, Rennes, France.
Alexandra
A
Traverse-Glehen
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Philippe
P
Gaulard
Departement of Hematology, Hospices Civils De Lyon, Lyon-1 University, Pierre Benite, CNRS UMR5239, France.
Diane
D
Damotte
Department of Pathology, Hôpitaux Universitaires, Paris Centre, Team « Cancer, Immune Control, and Escape » INSERM U1138, Cordeliers Research Center, Paris, France.
Richard
R
Delarue
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Corinne
C
Haioun
Department of Hematology, Necker Hospital, AP-HP, Paris, France.
Christian
C
Argueta
Department of Hematology, Necker Hospital, AP-HP, Paris, France.
Yosef
Y
Landesman
Karyopharm Therapeutics, Newton, MA.
Gilles
G
Salles
Department of Biostatistics, Hopital Necker, Paris, France.
Jean-Philippe
JP
Jais
Departement of Genomics, Functional Genomic Platforms, IRCL, Lille, France.
Martin
M
Figeac
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Christiane
C
Copie-Bergman
Department of Pathology, Necker Hospital, AP-HP, Paris, France.
Thierry Jo
TJ
Molina
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Jean Michel
JM
Picquenot
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Marie
M
Cornic
Departement of Hematology, Inserm U917, CHU Pontchaillou, Rennes, France.
Thierry
T
Fest
Department of Hematology, CHU De Bordeaux, France.
Noel
N
Milpied
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Emilie
E
Lemasle
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Aspasia
A
Stamatoullas
Department of Pathology, Institute of Pathology, University of Ulm, Germany.
Peter
P
Moeller
Department of Hematology, Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester, United Kingdom.
Martin J S
MJ
Dyer
Department of Pathology, Uppsala, Sweden.
Christer
C
Sundstrom
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Christian
C
Bastard
Departement of Hematology, Inserm U918, Centre Henri Becquerel, Rouen, France.
Hervé
H
Tilly
Departement of Hematology, Inserm U955 Team 09, APHP Hospital Henri Mondor, Créteil, France.
Karen
K
Leroy
D000179:Acrylates / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers; D045744:Cell Line, Tumor; D005260:Female; D020869:Gene Expression Profiling; D006689:Hodgkin Disease / Q000235:genetics; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008479:Mediastinal Neoplasms / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000502:physiology; D017422:Sequence Analysis, DNA; D014230:Triazoles / Q000494:pharmacology; D055815:Young Adult; D000097606:Exportin 1 Protein
D000179:Acrylates; D015415:Biomarkers; D006834:Hydrazines; D028884:Karyopherins; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C585161:selinexor