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Oncogene. 2019 Mar;38(13):2241-2262. doi: 10.1038/s41388-018-0567-7. Epub 2018 Nov 26.

Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.

Author information

1
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
2
NewAgeSys, Inc., Princeton Junction, NJ, USA.
3
Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
4
Institute of Research in Immunology and Cancer (IRIC), Department of Pathology and Cell Biology, Universite de Montreal, Montreal, QC, Canada.
5
Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
6
Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
7
Division of Hematology and Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA.
8
Division of Clinical Pharmacology & Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
9
Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA.
10
Therapy Acceleration Program, Leukemia & Lymphoma Society, Rye Brook, NY, USA.
11
Department of Pathology and UNM Cancer Center, University of New Mexico Health Services, Albuquerque, NM, USA.
12
Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
13
Department of Pathology, Ohio State University, Columbus, OH, USA.
14
Children's Oncology Group, Department of Biostatistics, Gainesville, FL, USA.
15
Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
16
Children's Hospital Colorado and The University of Colorado School of Medicine, Aurora, CO, USA.
17
Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA. felix@email.chop.edu.
18
Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA. felix@email.chop.edu.

Abstract

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.

PMID:
30478448
PMCID:
PMC6440839
DOI:
10.1038/s41388-018-0567-7
[Indexed for MEDLINE]
Free PMC Article

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