3 4 Running title 5 MYD88 splice variants in B cell lymphoma 6 7 Key points 8 ▪ In human B cells the TLR adaptor and oncogene MYD88 preferentially gives rise to NF-κB-9 promoting canonical splice variants. 10 ▪ B cells lack NF-κB-restriction by alternative MYD88 splicing, a critical negative feedback 11 loop in myeloid cells, favoring lymphomagenesis. 12 13 Abstract 14 Gain-of-function mutations of the TLR adaptor and oncoprotein MyD88 drive B cell 15 lymphomagenesis via sustained NF-κB activation. In myeloid cells, sustained TLR activation 16and NF-κB activation lead to the induction of inhibitory MYD88 splice variants that restrain 17 prolonged NF-κB activation. We therefore sought to investigate whether such a negative 18 feedback loop exists in B cells. Analyzing MYD88 splice variants in normal B cells and 19 different primary B cell malignancies, we observed that MYD88 splice variants in 20 transformed B cells are dominated by the canonical, strongly NF-κB-activating isoform of 21 MYD88 and contain at least three novel, so far uncharacterized signaling-competent splice 22 isoforms. TLR stimulation in B cells unexpectedly reinforces splicing of NF-κB-promoting, 23 canonical isoforms rather than the 'MyD88s', a negative regulatory isoform that is typically 24 induced by TLRs in myeloid cells. This suggests that an essential negative feedback loop 25 restricting TLR signaling in myeloid cells at the level of alternative splicing, is missing in B 26 cells, rendering B cells vulnerable to sustained NF-κB activation and eventual 27 lymphomagenesis. Our results uncover MYD88 alternative splicing as an unappreciated 28 promoter of B cell lymphomagenesis and provide a rationale why oncogenic MYD88 29 mutations are exclusively found in B cells.

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