Hijacking the Message: Insights from Targeting mRNA Export and Translation in AML

Cancer cells hijack RNA metabolism, including splicing, polyadenylation, nuclear export and translation, to change both the amount and the form of the proteins they produce. This creates therapeutic vulnerabilities beyond the mutations and translocations that have guided drug development in acute myeloid leukemia (AML), where outcomes remain poor. Using AML as a paradigm, this review focuses on two nodes of RNA metabolism: the eukaryotic translation initiation factor eIF4E, a cap-chaperone that escorts mRNAs through processing, export and translation, and CRM1/XPO1, the major nuclear exporter of proteins and select RNAs that partners with eIF4E for specific mRNA export activity. We describe the RNA biology dysregulated in patients, the mechanisms of the inhibitors that target these pathways, and their pre-clinical and clinical data across AML and other malignancies. Indeed, early-stage clinical trials in AML and other malignancies show promise, including the use of CRM1/XPO1 inhibitors (selinexor, eltanexor) and eIF4E inhibitors (including ribavirin and tomivosertib). We discuss how selecting patients by eIF4E status, confirming on-target activity, and designing rational combinations could improve next-generation therapies.