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 

机构地区：[1]Unite Mixte de Recherche Centre National de la Recherche Scientifique 7276,INSERM U1262-Controle de la Reponse Immune B et Lymphoproliferations,Universitede Limoges,Limoges,France [2]Institute of Human Genetics,CNRS-UM UMR9002,Department of Biological Haematology,CHU Montpellier,University of Montpellier,UFR Medecine,Montpellier,France [3]Institut Universitaire de France,Universitede Limoges,Limoges,France [4]Present address:Lady Davis Institute for Medical Research,McGill University,3755 Cote Ste-Catherine Road,Montreal,QC H3T 1E2,Canada

出　　处：《Cellular & Molecular Immunology》2019年第10期810-819,共10页中国免疫学杂志（英文版）

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).

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.

关 键 词：IMMUNOGLOBULIN Exon skipping Plasma cells Antisense Oligonucleotides Nonsense-associated altered splicing 

分 类 号：R73[医药卫生—肿瘤]