Some aggressive lymphomas switch their dependency from a common protein to one normally found only in the testis, and this project aims to turn that switch into a target for treatment. The problem is that the most aggressive forms of B-cell lymphoma, driven by the MYC oncogene, respond poorly to existing therapies. The researchers have discovered that in male patients, these cancer cells often inactivate the RNA helicase DDX3X and become dependent on its Y-chromosome counterpart, DDX3Y—a protein absent from nearly all healthy tissues. This makes DDX3Y a tumour-specific vulnerability, but its molecular functions remain poorly understood. This project will use genetically modified mice, engineered cell lines, and primary human B cells to map exactly what DDX3X and DDX3Y do in normal and malignant cells, and how the switch between them occurs. If successful, the work could lay the biological foundation for a new class of therapies that exploit DDX3Y dependency, potentially offering a more effective and less toxic treatment for aggressive lymphomas that currently have few options. The research is fundamental in nature—it builds the mechanistic understanding needed before any drug development can begin.
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Lymphoma is form of cancer arising most often from the malignant transformation of a specific type of immune system cell called the germinal centre B cell. The most aggressive subtypes of lymphoma are associated with genetic activation of the oncogene MYC, and respond poorly to available therapies. New treatments that are more effective and less toxic are urgently required. RNA helicases are proteins that unwind secondary structure within their target messenger RNAs. Recent data from our lab suggest the RNA helicase DDX3X and its Y-chromosome paralogue DDX3Y are at the centre of an intriguing lymphoma-specific vulnerability. We showed that male MYC-driven lymphoma cells often switch their dependency from the ubiquitous DDX3X, to the Y-chromosome prologue DDX3Y, a protein normally expressed only in the testis. This paralogue switch results from the genetic inactivation of DDX3X, followed by ectopic activation of DDX3Y. As a cancer-essential gene absent from normal cells, DDX3Y represents an exciting tumour-specific, therapeutic target. However, little is known about the molecular activity or regulation of DDX3Y. Despite a prior assumption of redundancy with DDX3X, emerging data suggests there may be important functional differences between the two paralogues. This project will investigate the functions of DDX3X and DDX3Y using a series of genetically modified mouse models, engineered cell lines and primary human B cells. These will be combined with advanced analytical techniques to determine the contrasting functions of the two helicases in normal and malignant B cells. This work will dissect the shared and paralogue-specific roles of DDX3X and DDX3Y in each stage of mRNA processing and elucidate the mechanisms of DDX3Y ectopic expression. In parallel, we will identify the synthetic vulnerabilities conferred upon lymphoma cells by the paralogue switch. Overall, this study will build the biological understanding required to exploit acquired DDX3Y-dependency as a novel therapeutic vulnerability of aggressive B cell lymphoma.
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