HNRNPU mutations redirect cell cycle control to E2F in MYC-driven lymphomas

Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is a ubiquitously expressed, pleiotropic DNA and RNA binding protein involved in RNA metabolism. Heterozygous HNRNPU nonsense mutations have been observed in a variety of B-cell lymphomas, but the functional consequence of these mutations remains largely unknown. Through a large meta-analysis of genome- and exome-wide sequencing data, we find that these mutations are more common among tumors with MYC rearrangements, including high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (12.1%), and Burkitt lymphoma (5.2%). Using isogenic cell line models, we demonstrate that HNRNPU is a haploinsufficient tumor suppressor, with inactivation of a single allele promoting cell cycle entry through widespread alteration of the gene expression and splicing landscape. We show that reduced hnRNPU expression consistently lowers MYC levels while simultaneously enhancing E2F-driven signaling. This creates a cellular state in which MYC-induced stress may be buffered while cell cycle progression is maintained. Finally, we show that owing to this increased dependence on E2Fs for proliferative signaling, 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.