PT  - JOURNAL ARTICLE
AU  - Marchalot, Anne
AU  - Lambert, Jean-Marie
AU  - Boyer, François
AU  - Pollet, Justine
AU  - Moreau, Jeanne
AU  - Feuillard, Jean
AU  - Faumont, Nathalie
AU  - Delpy, Laurent
TI  - Splice switching oligonucleotide mediated gene knockdown in B cells and plasma cells
AID  - 10.1101/2020.09.18.302984
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.18.302984
4099  - http://biorxiv.org/content/early/2020/09/18/2020.09.18.302984.short
4100  - http://biorxiv.org/content/early/2020/09/18/2020.09.18.302984.full
AB  - The need to identify new therapeutic approaches to the treatment of cancers of the B lymphoid lineage is crucial. Unlike CRISPR/Cas technology, antisense strategies result in transient modifications of gene expression and lack mutagenic effects at the DNA level. Here, we provide evidence for efficient knockdown of c-REL and RELA expression after treatment with splice switching antisense oligonucleotides (SSO) inducing exon skipping and reading frameshifts. We also developed a tool to facilitate the choice of exons for on purpose inhibition of mouse and human gene expression. Interestingly, treatments with morpholino SSO targeting the c-REL exon 2 donor splice site or RELA exon 5 acceptor splice site elicited very efficient knockdown in diffuse large B cell lymphoma (DLBCL) cell lines and antibody-secreting cells derived from primary human B cells. Consistent with the clinical relevance of c-REL activation in DLBCLs, treatment with c-REL SSO induced major alterations in NF-κB and TNF signalling pathways and strongly decreased cell viability. Altogether, SSO-mediated knockdown is a powerful approach to transiently inhibit the expression of given genes in B-lineage cells that should pave the way for cancer treatments, provided optimized ligand-conjugations for in vivo delivery.Competing Interest StatementThe authors have declared no competing interest.