Alternative splicing of its 5'-UTR limits CD20 mRNA translation and enables resistance to CD20-directed immunotherapies.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
16 Nov 2023
16 Nov 2023
Historique:
accepted:
19
08
2023
received:
08
03
2023
medline:
17
11
2023
pubmed:
8
9
2023
entrez:
8
9
2023
Statut:
ppublish
Résumé
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' 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 vitro 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.
Identifiants
pubmed: 37683180
pii: 497824
doi: 10.1182/blood.2023020400
pmc: PMC10667349
doi:
Substances chimiques
RNA, Messenger
0
5' Untranslated Regions
0
Antigens, CD20
0
Protein Isoforms
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1724-1739Subventions
Organisme : NCI NIH HHS
ID : U01 CA232563
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA243072
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA009615
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA232486
Pays : United States
Commentaires et corrections
Type : UpdateOf
Type : CommentIn
Informations de copyright
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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