Recurrent Mutations of the Exportin 1 Gene (XPO1) in Primary Mediastinal B-Cell Lymphoma: A Lysa Study

• Published in: Blood 2015-12, Vol.126 (23), p.129-129
• Main Authors: Jardin, Fabrice, Pujals, Anais, Pelletier, Laura, Bohers, Elodie, Camus, Vincent, Mareschal, Sylvain, Dubois, Sydney, Ochman, Marlène, Lemonnier, Francois, Viailly, Pierre-Julien, Bertrand, Philippe, Maingonnat, Catherine, Traverse-Glehen, Alexandra, Gaulard, Philippe, Damotte, Diane, Delarue, Richard, Haioun, Corinne, Landesman, Yosef, Senapedis, William, Argueta, Christian, Salles, Gilles Andre, Jais, Jean-Philippe, Figeac, Martin, Copie-Bergman, Christiane, Molina, Thierry, Picquenot, Jean-Michel, Cornic, Marie, Fest, Thierry, Milpied, Noel, Lemasle, Emilie, Stamatoullas, Aspasia, Moeller, Peter, Dyer, Martin JS, Sundstrom, Christer, Bastard, Christian, Tilly, Hervé, Leroy, Karen
• Format: Article
• Language: English
• Subjects: Life Sciences
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V126.23.129.129

Background and aim of the study Primary mediastinal B-cell lymphoma (PMBL) is an entity of aggressive B-cell lymphoma that is clinically and biologically distinct from the other molecular subtypes of diffuse large B-cell lymphoma (DLBCL). We recently detected by Whole exome sequencing a recurrent point mutation in the XPO1 (exportin 1) gene (also referred to as chromosome region maintenance 1; CRM1), which resulted in the Glu571Lys (p.E571K) missense substitution in 2 refractory/relapsed PMBL (Dubois et al., ICML 2015; Mareschal et al. AACR 2015). XPO1 is a member of the Karyopherin-b superfamily of nuclear transport proteins. XPO1 mediates the nuclear export of numerous RNAs and cellular regulatory proteins, including tumor suppressor proteins. This mutation is in the hydrophobic groove of XPO1 that binds to the leucine-rich nuclear export signal (NES) of cargo proteins. In this study, we investigated the prevalence, specificity, and biological / clinical relevance of XPO1 mutations in PMBL. Patients and methods High-throughput targeted or Sanger sequencing of 117 PMBL patients and 3 PMBL cell lines were performed. PMBL cases were defined either molecularly by gene expression profile (mPMBL cohort) or by standard histological method (hPMBL cohort) and enrolled in various LYSA (LYmphoma Study Association) clinical trials. To assess the frequency and specificity of XPO1 mutations, cases of classical Hodgkin lymphoma (cHL) and primary mediastinal grey zone lymphoma (MGZL) were analysed. Cell experiments were performed to assess the impact of the E571 mutation on the activity of selective inhibitor of nuclear export (SINE) molecules. Results XPO1 mutations were present in 28/117 (24%) PMBL cases but were rare in cHL cases (1/19, 5%) and absent from MGZL cases (0/20). A higher prevalence (50%) of the recurrent codon 571 variant (p.E571K) was observed in PMBL cases defined by gene expression profiling (n = 32), as compared to hPMBL cases (n = 85, 13%). No difference in age, International Prognostic Index (IPI) or bulky mass was observed between the PMBL patients harboring mutant and wild-type XPO1 in the overall cohort whereas a female predominance was noticed in the mPMBL cohort. Based on a median follow-up duration of 42 months, XPO1 mutant patients exhibited significantly decreased PFS (3y PFS = 74% [CI95% 55-100]) compared to wild-type patients (3y PFS = 94% [CI95% 83-100], p=0.049) in the mPMBL cohort. In 4/4 tested cases, the E571K variant was also detect