DISSECTING THE ROLE OF SETD2 IN GERMINAL CENTER DEVELOPMENT AND LYMPHOMAGENESIS

Abstract

SETD2, the protein responsible for histone 3, lysine 36 trimethylation, is highly expressed in germinal center B cells, mature B cell lymphomas and is recurrently mutated in DLBCL. We found that SETD2 haploinsufficiency results in germinal center hyperplasia and defective plasma cell differentiation following antigen stimulation. This was caused by decreased levels of apoptosis and accruing high levels DNA damage which was not effectively repaired. AICDA induced DNA damage occurring at the immunoglobulin locus and known non immunoglobulin target genes were found to be covered with Histone 3 lysine 36 trimethylation and following loss of SETD2, there were decreased levels of Histone 3 lysine 36 trimethylation and concomitant increase in mutations at these sites.SETD2 haploinsufficiency in combination with overexpression of the lymphoma oncogene, BCL2, resulted in the formation of aggressive B cell lymphomas with pathologic similarities to diffuse large B cell lymphomas. These tumors contained higher levels of mutations, clustered mutations, and structural variants, including the pathogenic IgH-MYC translocations, the genetic lesion driving the aggressive nature of these lymphomas. Collectively, our data indicate that SETD2, through the ability to trimethylated Histone 3 lysine 36, normally recruit DNA repair factors to sites of AICDA induced DNA damage and loss of SETD2 results in a hypermutator phenotype with increased number of mutations and structural variants, driving the formation of aggressive B cell lymphomas.