title: Protein synthesis is resistant to rapamycin and constitutes a promising therapeutic target in acute myeloid leukemia.
abstract: The deregulation of translation markedly contributes to the malignant phenotype in cancers, and the assembly of the translation initiating complex eIF4F is the limiting step of this process. The mammalian Target of Rapamycin Complex 1 (mTORC1) is thought to positively regulate eIF4F assembly and subsequent oncogenic protein synthesis through 4E-BP1 phosphorylation. We showed here that the translation inhibitor 4EGI-1 decreased the clonogenic growth of leukemic progenitors and induced apoptosis of blast cells, with limited toxicity against normal hematopoiesis, which emphasize the importance of translation deregulation in acute myeloid leukemia (AML) biology. However, the mTORC1 inhibitor RAD001 (a rapamycin derivate) did not induce AML blast cell apoptosis. We herein demonstrated that mTORC1 disruption using raptor siRNA or RAD001 failed to inhibit 4E-BP1 phosphorylation in AML. Moreover, RAD001 failed to inhibit eIF4F assembly, to decrease the proportion of polysome-bound c-Myc mRNA, and to reduce the translation-dependent accumulation of oncogenic proteins. We identified the Pim-2 serine/threonine kinase as mainly responsible for 4E-BP1 phosphorylation on the S(65) residue and subsequent translation control in AML. Our results strongly implicate an mTORC1-independent deregulation of oncogenic proteins synthesis in human myeloid leukemogenesis. Direct inhibition of the translation initiating complex thus represents an attractive option for the development of new therapies in AML.
authors.affiliation: Institut Cochin, Université Paris Descartes, Centre National de la Recherche Scientifique (CNRS, UMR8104), Paris, France.
authors.forename: Jerome
authors.initials: J
authors.lastname: Tamburini
authors.forename: Alexa S
authors.initials: AS
authors.lastname: Green
authors.forename: Valerie
authors.initials: V
authors.lastname: Bardet
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chapuis
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.forename: Lise
authors.initials: L
authors.lastname: Willems
authors.forename: Madalina
authors.initials: M
authors.lastname: Uzunov
authors.forename: Norbert
authors.initials: N
authors.lastname: Ifrah
authors.forename: François
authors.initials: F
authors.lastname: Dreyfus
authors.forename: Catherine
authors.initials: C
authors.lastname: Lacombe
authors.forename: Patrick
authors.initials: P
authors.lastname: Mayeux
authors.forename: Didier
authors.initials: D
authors.lastname: Bouscary
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D018797:Cell Cycle Proteins; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004351:Drug Resistance / Q000502:physiology*; D000068338:Everolimus; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D006835:Hydrazones; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D009574:Nitro Compounds / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D011506:Proteins; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology* / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles / Q000494:pharmacology; D014157:Transcription Factors / Q000378:metabolism
chemical_list: C517852:4EGI-1 compound; D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D006835:Hydrazones; D046912:Multiprotein Complexes; D009574:Nitro Compounds; D010750:Phosphoproteins; D011500:Protein Synthesis Inhibitors; D011506:Proteins; D013844:Thiazoles; D014157:Transcription Factors; D000068338:Everolimus; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus