Molecular alterations and tumor suppressive function of the DUSP22 (Dual Specificity Phosphatase 22) gene in peripheral T-cell lymphoma subtypes

// Pierre Melard 1, 2, * , Yamina Idrissi 1, * Laetitia Andrique 1, 3 , Sandrine Poglio 1 , Martina Prochazkova-Carlotti 1 , Sabine Berhouet 3 , Cecile Boucher 3 , Elodie Laharanne 1, 3 , Edith Chevret 1 , Anne Pham-Ledard 1, 4 , Andrea Carla De Souza Goes 1, 5 , Veronique Guyonnet-Duperat 6 , Alice Bibeyran 6 , Francois Moreau-Gaudry 6, 7 , Beatrice Vergier 1, 2 , Marie Beylot-Barry 1, 4 , Jean-Philippe Merlio 1, 3 , David Cappellen 1, 3 1 Institut National de la Sante et de la Recherche Medicale (Inserm) U1053, Universitaire de Bordeaux, F-33076 Bordeaux, France 2 Service de Pathologie, Centre Hospitalier Universitaire de Bordeaux, Hopital Haut-Leveque, F-33604 Pessac, France 3 Service de Biologie des Tumeurs-Tumorotheque, Centre Hospitalier Universitaire de Bordeaux, Hopital Haut-Leveque, F-33604 Pessac, France 4 Service de Dermatologie, Centre Hospitalier Universitaire de Bordeaux, Hopital Saint-Andre, F-33000 Bordeaux, France 5 Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro, CEP 20550-013 Rio de Janeiro, Brazil 6 Plateforme de Vectorologie, Unite Mixte de Services (UMS TBM-Core), Centre National de la Recherche Scientifique (CNRS)- Institut National de la Sante et de la Recherche Medicale (Inserm)-Universitaire de Bordeaux, F-33076 Bordeaux, France 7 Biotherapies des Maladies Genetiques et Cancers, Institut National de la Sante et de la Recherche Medicale (Inserm), U1035, Universitaire de Bordeaux, F-33076 Bordeaux, France * These authors have contributed equally to this work Correspondence to: David Cappellen, email: david.cappellen@u-bordeaux.fr Jean-Philippe Merlio, email: jp.merlio@u-bordeaux.fr Keywords: T-cell lymphomas, DUSP22, silencing, mutations, tumor suppressor function Received: April 28, 2016     Accepted: August 31, 2016     Published: September 10, 2016 ABSTRACT Monoallelic 6p25.3 rearrangements associated with DUSP22 (Dual Specificity Phosphatase 22 ) gene silencing have been reported in CD30+ peripheral T-cell lymphomas (PTCL), mostly with anaplastic morphology and of cutaneous origin. However, the mechanism of second allele silencing and the putative tumor suppressor function of DUSP22 have not been investigated so far. Here, we show that the presence, in most individuals, of an inactive paralog hampers genetic and epigenetic evaluation of the DUSP22 gene. Identification of DUSP22 -specific single-nucleotide polymorphisms haplotypes and fluorescence in situ hybridization and epigenetic characterization of the paralog status led us to develop a comprehensive strategy enabling reliable identification of DUSP22 alterations. We showed that one cutaneous anaplastic large T-cell lymphomas (cALCL) case with monoallelic 6p25.3 rearrangement and DUSP22 silencing harbored exon 1 somatic mutations associated with second allele inactivation. Another cALCL case carried an intron 1 somatic splice site mutation with predicted deleterious exon skipping effect. Other tested PTCL cases with 6p25.3 rearrangement exhibited neither mutation nor deletion nor methylation accounting for silencing of the non-rearranged DUSP22 allele, thus inactivated by a so far unknown mechanism. We also characterized the expression status of four DUSP22 splice variants and found that they are all silenced in cALCL cases with 6p25.3 breakpoints. We finally showed that restoring expression of the physiologically predominant isoform in DUSP22-deficient malignant T cells inhibits cellular expansion by stimulating apoptosis and impairs soft agar clonogenicity and tumorigenicity. This study therefore shows that DUSP22 behaves as a tumor suppressor gene in PTCL.