Abstract PO-19: Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis

DDX3X is a ubiquitously expressed RNA helicase involved in multiple stages of RNA biogenesis. DDX3X is frequently mutated in Burkitt lymphoma, but the functional basis for this is unknown. Here, we show that loss-of-function DDX3X mutations are also commonly found in MYC-translocated diffuse large B-cell lymphoma. We reveal functional cooperation between mutant DDX3X and MYC in ex vivo cultured human germinal center B cells. By integrating results of iCLIP, ribosome profiling, and proteomics, we show WT DDX3X promotes the translation of mRNAs encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations act to buffer the effect of abrupt MYC expression and moderate MYC-driven global protein synthesis, thereby buffering MYC-induced proteotoxic stress during early lymphomagenesis. Established lymphoma cells subsequently restore full protein synthetic capacity by aberrant expression of DDX3Y, a Y-chromosome homologue that is normally expressed exclusively in testis. These findings show how sequential dysregulation of DDX3X and DDX3Y acts to titrate global protein synthesis to suit the stage-specific needs of developing lymphoma cells and identify DDX3Y as an attractive, male-specific therapeutic target absent from normal human B cells but required for the survival of male lymphomas.

Citation Format: Chun Gong, Joanna A. Krupka, Jane Gao, Nicholas F. Grigoropoulos, Francesco Cucco, Sharon Barrans, De Los Mozos Igor, Zhou Peixun, Forde Sorca, Matthews Jamie, Burke Amos, Sze Siu Kwan, Beer Philip, Burton Cathy, Campbell Peter, Rand Vikki, Turner Suzanne, Ule Jernej, Roman Eve, Tooze Reuben, Oellerich Thomas, Du Ming, Samarajiwa Shamith, Daniel J. Hodson. Sequential inverse dysregulation of the RNA helicases DDX3X and DDX3Y facilitates MYC-driven lymphomagenesis [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-19.