The failure of B cells to induce non-canonical MYD88 splice variants correlates with lymphomagenesis via sustained NF-κB signaling

Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell lymphomagenesis via sustained NF-κB activation. In myeloid cells, sustained TLR activation and NF-κB activation lead to the induction of inhibitory splice variants that restrain prolonged NF-κB activation. We therefore sought to investigate whether such a negative feedback loop exists in B cells. Analyzing splice variants in normal B cells and different primary B cell malignancies, we observed that splice variants in transformed B cells are dominated by the canonical, strongly NF-κB-activating isoform of and contain at least three novel, so far uncharacterized signaling-competent splice isoforms. TLR stimulation in B cells unexpectedly reinforces splicing of NF-κB-promoting, canonical isoforms rather than the ‘MyD88s’, a negative regulatory isoform that is typically induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B cells, rendering B cells vulnerable to sustained NF-κB activation and eventual lymphomagenesis. Our results uncover alternative splicing as an unappreciated promoter of B cell lymphomagenesis and provide a rationale why oncogenic mutations are exclusively found in B cells.