Targeting EIF4E signaling with ribavirin in infant acute lymphoblastic leukemia.
Cell Line, Tumor
Child, Preschool
Drug Resistance, Neoplasm
/ drug effects
Eukaryotic Initiation Factor-4E
/ genetics
Gene Expression Profiling
Gene Expression Regulation, Leukemic
/ drug effects
Humans
Indoles
Infant
Microarray Analysis
Molecular Targeted Therapy
/ methods
Multigene Family
/ drug effects
Precursor Cell Lymphoblastic Leukemia-Lymphoma
/ diagnosis
Protein Biosynthesis
/ drug effects
Pyrroles
/ therapeutic use
Ribavirin
/ therapeutic use
Signal Transduction
/ drug effects
Journal
Oncogene
ISSN: 1476-5594
Titre abrégé: Oncogene
Pays: England
ID NLM: 8711562
Informations de publication
Date de publication:
03 2019
03 2019
Historique:
received:
07
06
2017
accepted:
11
10
2018
revised:
17
08
2018
pubmed:
28
11
2018
medline:
14
5
2019
entrez:
28
11
2018
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30478448
doi: 10.1038/s41388-018-0567-7
pii: 10.1038/s41388-018-0567-7
pmc: PMC6440839
mid: NIHMS1509636
doi:
Substances chimiques
Eukaryotic Initiation Factor-4E
0
Indoles
0
Pyrroles
0
Ribavirin
49717AWG6K
obatoclax
QN4128B52A
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2241-2262Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : U24CA114766
Pays : International
Organisme : NCI NIH HHS
ID : U10 CA098413
Pays : United States
Organisme : EIF | Stand Up To Cancer (SU2C)
ID : SU2C-AACR-DT1113
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA98571
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA198089
Pays : International
Organisme : Alex's Lemonade Stand Foundation for Childhood Cancer (Alex's Lemonade Stand Foundation)
ID : N/A
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : U10CA98413
Pays : International
Organisme : NCI NIH HHS
ID : U10 CA180886
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA098571
Pays : United States
Organisme : NCI NIH HHS
ID : U10 CA180899
Pays : United States
Organisme : American Cancer Society (American Cancer Society, Inc.)
ID : ACS MRSG-12-215-01-LIB
Pays : International
Organisme : American Society of Hematology (ASH)
ID : Bridge Grant; N/A
Pays : International
Organisme : NCI NIH HHS
ID : U24 CA114766
Pays : United States
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : K08CA184418
Pays : International
Organisme : NCI NIH HHS
ID : R01 CA080728
Pays : United States
Organisme : Leukemia and Lymphoma Society (LLS)
ID : SCOR 7372-07
Pays : International
Organisme : U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)
ID : R01CA080728
Pays : International
Organisme : NCI NIH HHS
ID : K08 CA184418
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA198089
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA016520
Pays : United States
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