A novel mechanism for Bcr-Abl action: Bcr-Abl-mediated induction of the eIF4F translation initiation complex and mRNA translation.
The oncogenic kinase Bcr-Abl is thought to cause chronic myelogenous leukemia (CML) by altering the transcription of specific genes with growth- and survival-promoting functions. Recently, Bcr-Abl has also been shown to activate an important regulator of protein synthesis, the mammalian target of rapamycin (mTOR), which suggests that dysregulated translation may also contribute to CML pathogenesis. In this study, we found that both Bcr-Abl and the rapamycin-sensitive mTORC1 complex contribute to the phosphorylation (inactivation) of 4E-BP1, an inhibitor of the eIF4E translation initiation factor. Experiments with rapamycin and the Bcr-Abl inhibitor, imatinib mesylate, in Bcr-Abl-expressing cell lines and primary CML cells indicated that Bcr-Abl and mTORC1 induced formation of the translation initiation complex, eIF4F. This was characterized by reduced 4E-BP1 binding and increased eIF4G binding to eIF4E, two events that lead to the assembly of eIF4F. One target transcript is cyclin D3, which is regulated in Bcr-Abl-expressing cells by both Bcr-Abl and mTORC1 in a translational manner. In addition, the combination of imatinib and rapamycin was found to act synergistically against committed CML progenitors from chronic and blast phase patients. These experiments establish a novel mechanism of action for Bcr-Abl, and they provide insights into the modes of action of imatinib mesylate and rapamycin in treatment of CML. They also suggest that aberrant cap-dependent mRNA translation may be a therapeutic target in Bcr-Abl-driven malignancies.
Prabhu
S
S
The Division of Hematology/Oncology, University of California, Irvine, CA 92697, USA.
Saadat
D
D
Zhang
M
M
Halbur
L
L
Fruehauf
J P
JP
Ong
S T
ST
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D002352:Carrier Proteins / Q000378:metabolism; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins / Q000378:metabolism; D039562:Eukaryotic Initiation Factor-4F / Q000378:metabolism*; D039603:Eukaryotic Initiation Factor-4G / Q000378:metabolism; D039642:Eukaryotic Initiation Factors; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism*; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D014176:Protein Biosynthesis / Q000187:drug effects; D011506:Proteins; D011743:Pyrimidines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; C534696:CCND3 protein, human; D002352:Carrier Proteins; C534697:Ccnd3 protein, mouse; D018797:Cell Cycle Proteins; D056743:Cyclin D3; D016213:Cyclins; C499527:Eif4ebp1 protein, mouse; D039562:Eukaryotic Initiation Factor-4F; D039603:Eukaryotic Initiation Factor-4G; D039642:Eukaryotic Initiation Factors; D046912:Multiprotein Complexes; D010750:Phosphoproteins; D010879:Piperazines; D011506:Proteins; D011743:Pyrimidines; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus