Abstract
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 and reveal functional co-operation between mutant DDX3X and MYC. DDX3X promotes translation of mRNAs encoding components of the core translational machinery, thereby driving global protein synthesis. Loss-of-function DDX3X mutations 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 that DDX3X loss-of-function can buffer MYC-driven proteotoxic stress, and highlight the capacity of male B cell lymphomas to later compensate for this loss by ectopic DDX3Y expression.
Highlights
Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma, with a 3:1 male:female incidence ratio (Morton et al, 2006; Smith et al, 2015)
DDX3X is preferentially mutated in MYC-driven lymphomas We applied targeted sequencing to 39 cases of BL
When the same targeted panel and variant calling strategy was applied to 928 cases of diffuse large B cell lymphoma (DLBCL), we detected DDX3X mutation in only 5.2% (Lacy et al, 2020), a figure similar to that of other recent DLBCL sequencing studies (Figure 1B) (Chapuy et al, 2018; Reddy et al, 2017; Schmitz et al, 2018)
Summary
Burkitt lymphoma (BL) is an aggressive non-Hodgkin lymphoma, with a 3:1 male:female incidence ratio (Morton et al, 2006; Smith et al, 2015). The oncoprotein MYC is required for this process, but its expression is transient and limited to a minority of GC B cells undergoing positive selection (Calado et al, 2012; Dominguez-Sola et al, 2012). An unwanted by-product of CSR is the risk of translocation of the MYC oncogene into the immunoglobulin loci leading to sustained and high-level expression of MYC. Many cases of MYC-translocated DLBCL fall into the molecular high-grade (MHG) transcriptional subtype (Painter et al, 2019; Sha et al, 2019). Those cases of MHG without detectable MYC rearrangement frequently possess cryptic alterations leading to the deregulation of MYC expression (Hilton et al, 2019). Mouse models reveal that high-level MYC expression alone is insufficient to drive lymphomagenesis, and further cooperating genetic events are required (Sander et al, 2012)
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