The eukaryotic translation initiation factor eIF4E drives the expression of proteins involved in proliferation and survival. eIF4E mediates these effects through its biochemical activities in the translation and nuclear export of specific transcripts through interaction with the m7G cap on the 5' end of mRNAs. During the past 10 years of funding, we have demonstrated that the mRNA export function of eIF4E contributes to its oncogenic potential. Our studies led to the identification of a cap competitor, ribavirin, whic suppresses eIF4E dependent mRNA export in the laboratory and in two clinical trials in poor prognosis M4/M5 AML patients. In our clinical trials, eIF4E targeting corresponded to clinical responses including remissions. Given its clear relevance, we initiated studies to dissect the molecular underpinnings of eIF4E mediated RNA export. For eIF4E to function in mRNA export it must be re-cycled into the nucleus after each export event. Anything that would impair this step, impairs the entire process. However, virtually nothing is known about this aspect of eIF4E trafficking. Here, we identify two factors that control the nuclear localization of eIF4E: Importin8 and eIF4E3. We observe that Importin 8 directly binds eIF4E and imports it into the nucleus. Using NMR, we identified a molecular switch, whereby ribavirin or m7G cap binding lead to structural changes in eIF4E which impair the Importin 8-eIF4E association, nuclear entry and mRNA export. This correlates with repression of eIF4E oncogenic activities in cell culture. Next, we identified a novel eIF4E family member, eIF4E3, which appears to regulate this nuclear entry step. eIF4E3 represses Importin 8 production, eIF4E dependent mRNA export and eIF4E mediated oncogenic transformation in cells. These factors are clinically relevant since we observe that Importin 8 is elevated and eIF4E3 reduced in AML. Taken together, these findings provide a framework for understanding eIF4E trafficking during clinical response and relapse. We hypothesize that the subcellular trafficking of eIF4E is a critical control point for its mRNA export function and thereby underlies its oncogenic potential. We postulate that elucidating the molecular underpinnings and regulation of this process will provide novel insights into the underlying basis of eIF4E mediated-oncogenic transformation. PUBLIC HEALTH RELEVANCE: eIF4E is elevated in an estimated 30% of cancers including acute myeloid leukemias (AML) of the M4 and M5 subtype. Studies of eIF4E elevation in cell culture and animal models demonstrate that it is a potent oncogene. Targeting of eIF4E led to remissions in some AML patients thus understanding its molecular activities is important.