Abstract: The need to identify new therapeutic approaches in the treatment of cancers of the B lymphoid lineage is crucial. Here, the inventors provide evidence for efficient knockdown of c-REL and RELA expression after treatment with splice switching antisense oligonucleotides (SSO) inducing exon skipping and reading frameshift. For instance, treatments with morpholino SSO targeting 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 DLBCL, treatment with c-REL SSO induced major alterations in NF-?B and TNF signalling pathways and strongly decreased cell viability. Altogether, SSO-mediated knockdown is a powerful approach to inhibit transiently the expression of a NF-?B component in B-lineage cells that should open new avenues for cancer treatments.