Oncogenic Impact of eIF4E-dependent RNA Export in Cancer

Abstract This renewal application investigates the impact of dysregulated RNA processing in cancer. Dysregulation of these events can elevate the production of proteins that function in all facets of malignancy, without altering their transcript levels. The eukaryotic translation initiation factor eIF4E, dysregulated in many cancers including in acute myeloid leukemia (AML), governs the RNA processing of networks of transcripts that ultimately underpin its oncogenic activities. Its ability to govern these regulons has been attributed to its well-established roles in nuclear export and translation of specific RNAs. eIF4E elevation in cancer patients is correlated with aggressive disease and poor outcomes. Here, we discovered that eIF4E reprograms various facets of cell motility including adherence, migration, and invasion through its effects on RNA processing. Indeed, we identified eIF4E-dependent RNA export targets that encode factors which are key modulators of cell motility including hyaluronan, its main receptor CD44 and ezrin. Ezrin is an intracellular protein that links CD44 signalling to cytoskeletal changes that alter adherence, migration, and invasion. Furthermore, eIF4E directly interacts with ezrin. Three aims are proposed to dissect the mechanistic principles and biological impacts related to these novel findings. We will uncover the requirements for eIF4E to drive cell movement, determine the role of the ezrin- eIF4E complex in translation and motility, and examine the role of the HA/CD44/ezrin axis in eIF4E-dependent AML cell motility in mouse models. Our studies provide a unique opportunity to identify novel biochemical mechanisms that underpin aggressive disease associated with dysregulated eIF4E.