Physiological and druggable skipping of immunoglobulin variable exons in plasma cells

作     者：Mohamad Omar Ashi Nivine Srour Jean-Marie Lambert Anne Marchalot Ophelie Martin Sandrine Le Noir Eric Pinaud Maria Victoria Ayala Christophe Sirac Jerome Sauliere Jerome Moreaux Michel Cogne Laurent Delpy 

作者机构：Unite Mixte de Recherche Centre National de la Recherche Scientifique 7276INSERM U1262-Controle de la Reponse Immune B et LymphoproliferationsUniversitede LimogesLimogesFrance Institute of Human GeneticsCNRS-UM UMR9002Department of Biological HaematologyCHU MontpellierUniversity of MontpellierUFR MedecineMontpellierFrance Institut Universitaire de FranceUniversitede LimogesLimogesFrance Present address:Lady Davis Institute for Medical ResearchMcGill University3755 Cote Ste-Catherine RoadMontrealQC H3T 1E2Canada 

出 版 物：《Cellular & Molecular Immunology》 (中国免疫学杂志（英文版）)

年 卷 期：2019年第16卷第10期

页      面：810-819页

核心收录：

学科分类：0710[理学-生物学] 1004[医学-公共卫生与预防医学(可授医学、理学学位)] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by grants from Fondation ARC(PJA 20161204724/PGA120150202338) INCa(PLBIO15-256) ANR(2017-CE15-0024-01) Ligue Contre le Cancer(comites Correze,Haute-Vienne) Fondation Française pour la Recherche contre le Myelome et les Gammapathies monoclonales(FFRMG) Comited’Organisation de la Recherche sur le Cancer du Limousin(CORC). 

主　　题：Immunoglobulin Exon skipping Plasma cells Antisense Oligonucleotides Nonsense-associated altered splicing 

摘      要：The error-prone V(D)J recombination process generates considerable amounts of nonproductive immunoglobulin(Ig)pre-mRNAs.We recently demonstrated that aberrant Ig chains lacking variable(V)domains can be produced after nonsense-associated altered splicing(NAS)events.Remarkably,the expression of these truncated Ig polypeptides heightens endoplasmic reticulum stress and shortens plasma cell(PC)lifespan.Many questions remain regarding the molecular mechanisms underlying this new truncated Ig exclusion(TIE-)checkpoint and its restriction to the ultimate stage of B-cell differentiation.To address these issues,we evaluated the extent of NAS of Ig pre-mRNAs using an Ig heavy chain(IgH)knock-in model that allows for uncoupling of V exon skipping from TIE-induced apoptosis.We found high levels of V exon skipping in PCs compared with B cells,and this skipping was correlated with a biallelic boost in IgH transcription during PC differentiation.Chromatin analysis further revealed that the skipped V exon turned into a pseudo-intron.Finally,we showed that hypertranscription of Ig genes facilitated V exon skipping upon passive administration of splice-switching antisense oligonucleotides(ASOs).Thus,V exon skipping is coupled to transcription and increases as PC differentiation proceeds,likely explaining the late occurrence of the TIE-checkpoint and opening new avenues for ASO-mediated strategies in PC disorders.