Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia

Abstract

Dysregulation of mRNA translation leads to aberrant activation of cellular pathways that promote expansion and survival of leukemic clones. A key element of the initiation translation complex is eIF4E (eukaryotic translation initiation factor 4E). The mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) pathways play important roles in the regulation of eIF4E expression and downstream functional outcomes. Mitogen-activated protein kinase interacting protein kinases (Mnks) control translation by phosphorylation of eIF4E, whereas the mTOR kinase phosphorylates/de-activates the eIF4E inhibitor, 4E-BP1, to release translational repression. Both pathways are often abnormally activated in leukemia cells and promote cell survival events by controlling expression of oncogenic proteins. Targeting these pathways may provide approaches to avoid aberrant proliferation and neoplastic transformation.

Keywords: Acute myeloid leukemia; MNK; Translation initiation; eIF4E; mTOR.

Figure 1

Schematic illustration depicting the cellular pathways that lead to eIF4E activation.