Functional characterization of recurrent HNRNPU mutations in MYC-driven aggressive lymphomas

hnRNPU is a ubiquitously expressed, pleiotropic DNA and RNA binding protein involved in RNA metabolism. It is recurrently mutated in Burkitt and high-grade B-cell lymphomas, but the functional consequence of this recurrence is unknown. Here, I show that heterozygous HNRNPU nonsense mutations are enriched in lymphomas with MYC translocations. The results imply that HNRNPU is haploinsufficient and mutations of a single allele promote cell cycle entry by altering the gene expression and splicing landscape of the B cells that harbor them. This reduced hnRNPU expression lowers MYC levels, possibly to buffer MYC-induced proteotoxic stress and shifts dependence from MYC to E2Fs to maintain cell cycle promotion. Finally, I show that, owing to this dependence on E2Fs for cell cycle progression, HNRNPU mutated lymphomas are more sensitive to E2F inhibitors. These results highlight hnRNPU-mediated regulation of MYC and its downstream effects as possible new avenues for therapeutic intervention in MYC-driven lymphomas.