SETD2 haploinsufficiency enhances germinal center-associated AICDA somatic hypermutation to drive B cell lymphomagenesis

SETD2 is the sole chromatin modifier responsible for H3K36me3, a histone mark linked to splicing, transcription initiation and DNA damage response. Homozygous disruption of SETD2 yields a tumor suppressor effect in various cancers. However, SETD2 mutation is virtually always heterozygous in diffuse large B-cell lymphomas (DLBCL). Here we show that heterozygous SETD2 deficiency results in germinal center (GC) hyperplasia and accelerated lymphomagenesis. SETD2 haploinsufficient GC B-cells exhibit increased competitive fitness and reduced DNA damage checkpoint activity, resulting in decreased apoptosis. SETD2 haploinsufficient GCB and lymphoma cells featured increased off- and on-target AICDA induced somatic hypermutation (SHM), complex structural variants such as rygma, and increased translocations including those activating MYC. DNA damage was selectively increased on the non-template strand and H3K36me3 loss was associated with greater RNA Pol II processivity and mutational burden, suggesting that SETD2-mediated H3K36me3 is required for proper sensing of cytosine deamination during transcription. Hence, SETD2 haploinsufficiency delineates a novel GC B-cell context specific oncogenic pathway involving defective epigenetic surveillance of AICDA mediated somatic hypermutation induced off target effects on transcribed genes.