Journal
ONCOGENE
Volume 38, Issue 13, Pages 2241-2262Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0567-7
Keywords
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Funding
- Leukemia & Lymphoma Society [SCOR 7372-07]
- ASH Bridge Funding Program
- CHOP Bridge Funding Program
- Eagles Fly for Leukemia
- CHOP Hematologic Malignancies Research Fund
- SU2C St. Baldrick's Pediatric Dream Team Translational Research [SU2C-AACR-DT1113]
- Cookies for Kids' Cancer Foundation
- Rally Foundation [K08CA184418]
- Hyundai Hope on Wheels Scholar Award [ACS MRSG-12-215-01-LIB]
- Canada Research Chair [R01CA098571, R01CA080728]
- COG Statistical Center [U10CA98413]
- COG Specimen Banking [U24CA114766]
- [R01CA198089]
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The poor outcomes in infant acute lymphoblastic leukemia (ALL) necessitate new treatments. Here we discover that EIF4E protein is elevated in most cases of infant ALL and test EIF4E targeting by the repurposed antiviral agent ribavirin, which has anticancer properties through EIF4E inhibition, as a potential treatment. We find that ribavirin treatment of actively dividing infant ALL cells on bone marrow stromal cells (BMSCs) at clinically achievable concentrations causes robust proliferation inhibition in proportion with EIF4E expression. Further, we find that ribavirin treatment of KMT2A-rearranged (KMT2A-R) infant ALL cells and the KMT2A-AFF1 cell line RS4:11 inhibits EIF4E, leading to decreases in oncogenic EIF4E-regulated cell growth and survival proteins. In ribavirin-sensitive KMT2A-R infant ALL cells and RS4:11 cells, EIF4E-regulated proteins with reduced levels of expression following ribavirin treatment include MYC, MCL1, NBN, BCL2 and BIRC5. Ribavirin-treated RS4:11 cells exhibit impaired EIF4E-dependent nuclear to cytoplasmic export and/or translation of the corresponding mRNAs, as well as reduced phosphorylation of the p-AKT1, p-EIF4EBP1, p-RPS6 and p-EIF4E signaling proteins. This leads to an S-phase cell cycle arrest in RS4:11 cells corresponding to the decreased proliferation. Ribavirin causes nuclear EIF4E to re-localize to the cytoplasm in KMT2A-AFF1 infant ALL and RS4:11 cells, providing further evidence for EIF4E inhibition. Ribavirin slows increases in peripheral blasts in KMT2A-R infant ALL xenograft-bearing mice. Ribavirin cooperates with chemotherapy, particularly L-asparaginase, in reducing live KMT2A-AFF1 infant ALL cells in BMSC co-cultures. This work establishes that EIF4E is broadly elevated across infant ALL and that clinically relevant ribavirin exposures have preclinical activity and effectively inhibit EIF4E in KMT2A-R cases, suggesting promise in EIF4E targeting using ribavirin as a means of treatment.
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