{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T22:02:20Z","timestamp":1790978540933,"version":"4.1.0"},"reference-count":88,"publisher":"American Society of Hematology","issue":"20","license":[{"start":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T00:00:00Z","timestamp":1694131200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,11,16]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Aberrant skipping of coding exons in CD19 and CD22 compromises the response to immunotherapy in B-cell malignancies. Here, we showed that the MS4A1 gene encoding human CD20 also produces several messenger RNA (mRNA) isoforms with distinct 5\u2032 untranslated regions. Four variants (V1-4) were detected using RNA sequencing (RNA-seq) at distinct stages of normal B-cell differentiation and B-lymphoid malignancies, with V1 and V3 being the most abundant. During B-cell activation and Epstein-Barr virus infection, redirection of splicing from V1 to V3 coincided with increased CD20 positivity. Similarly, in diffuse large B-cell lymphoma, only V3, but not V1, correlated with CD20 protein levels, suggesting that V1 might be translation-deficient. Indeed, the longer V1 isoform contained upstream open reading frames and a stem-loop structure, which cooperatively inhibited polysome recruitment. By modulating CD20 isoforms with splice-switching morpholino oligomers, we enhanced CD20 expression and anti-CD20 antibody rituximab-mediated cytotoxicity in a panel of B-cell lines. Furthermore, reconstitution of CD20-knockout cells with V3 mRNA led to the recovery of CD20 positivity, whereas V1-reconstituted cells had undetectable levels of CD20 protein. Surprisingly, in\u00a0vitro CD20-directed chimeric antigen receptor T cells were able to kill both V3- and V1-expressing cells, but the bispecific T-cell engager mosunetuzumab was only effective against V3-expressing cells. To determine whether CD20 splicing is involved in immunotherapy resistance, we performed RNA-seq on 4 postmosunetuzumab follicular lymphoma relapses and discovered that in 2 of them, the downregulation of CD20 was accompanied by a V3-to-V1 shift. Thus, splicing-mediated mechanisms of epitope loss extend to CD20-directed immunotherapies.<\/jats:p>","DOI":"10.1182\/blood.2023020400","type":"journal-article","created":{"date-parts":[[2023,9,8]],"date-time":"2023-09-08T16:03:33Z","timestamp":1694189013000},"page":"1724-1739","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":58,"title":["Alternative splicing of its 5\u2032-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies"],"prefix":"10.1182","volume":"142","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6583-4733","authenticated-orcid":false,"given":"Zhiwei","family":"Ang","sequence":"first","affiliation":[{"name":"1Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6505-0194","authenticated-orcid":false,"given":"Luca","family":"Paruzzo","sequence":"additional","affiliation":[{"name":"2Center for Cellular Immunotherapies, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"},{"name":"3Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA"},{"name":"4Division of Hematology\/Oncology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-3111","authenticated-orcid":false,"given":"Katharina E.","family":"Hayer","sequence":"additional","affiliation":[{"name":"5Department of Biomedical and Health Informatics, Children's Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Schmidt","sequence":"additional","affiliation":[{"name":"1Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5487-8113","authenticated-orcid":false,"given":"Manuel","family":"Torres Diz","sequence":"additional","affiliation":[{"name":"1Division of Cancer Pathobiology, Children's Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Xu","sequence":"additional","affiliation":[{"name":"6Division of Genomic Diagnostic, Children's Hospital of Philadelphia, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urvi","family":"Zankharia","sequence":"additional","affiliation":[{"name":"7Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, 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Sainos","sequence":"additional","affiliation":[{"name":"9Department of Biology, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinodh","family":"Pillai","sequence":"additional","affiliation":[{"name":"10Division of Hematopathology, Children's Hospital of Philadelphia, Philadelphia, PA"},{"name":"11Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA"},{"name":"12Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emeline","family":"Chong","sequence":"additional","affiliation":[{"name":"3Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marilyn M.","family":"Li","sequence":"additional","affiliation":[{"name":"6Division of Genomic Diagnostic, Children's 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