Dual targeting of eIF4E by blocking MNK and mTOR pathways in leukemia.
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.
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA. Electronic address: ewa.kosciuczuk@northwestern.edu.
Ewa M
EM
Kosciuczuk
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Diana
D
Saleiro
Robert H. Lurie Comprehensive Cancer Center and Division of Hematology-Oncology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA; Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA.
Leonidas C
LC
Platanias
D000818:Animals; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
D039561:Eukaryotic Initiation Factor-4E; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; C000601282:eIF4E protein, mouse; C546842:MTOR protein, human; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
Acute myeloid leukemia; MNK; Translation initiation; eIF4E; mTOR