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

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• 作者：Fabrice Jardin ; Anais Pujals ; Laura Pelletier ; Elodie Bohers ; Vincent Camus ; Sylvain Mareschal ; Sydney Dubois ; Brigitte Sola ; Marlè ; ne Ochmann ; Franç ; ois Lemonnier ; Pierre-Julien Viailly ; Philippe Bertrand ; Catherine Maingonnat ; Alexandra Traverse-Glehen ; Philippe Gaulard ; Diane Damotte ; Richard Delarue ; Corinne Haioun ; Christian Argueta ; Yosef Landesman ; Gilles Salles ; Jean-Philippe Jais ; Martin Figeac ; Christiane Copie-Bergman ; Thierry Jo Molina ; Jean Michel Picquenot ; Marie Cornic ; Thierry Fest ; Noel Milpied ; Emilie Lemasle ; Aspasia Stamatoullas ; Peter Moeller ; Martin J.S Dyer ; Christer Sundstrom ; Christian Bastard ; Hervé ; Tilly and Karen Leroy
• 刊名：American Journal of Hematology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：91
• 期：9
• 页码：923-930
• 全文大小：622K
• ISSN：1096-8652

文摘

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.