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.

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Additional information

These authors contributed equally: Katherine L. B. Borden, Carolyn A. Felix (co-senior authors).

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Acknowledgements

Childhood ALL samples provided by CHOP CCCR Biorepository. CAF is Joshua Kahan Endowed Chair in Pediatric Leukemia Research. SPH is Jeffrey E. Perelman Distinguished Chair in the Department of Pediatrics at CHOP. KLBB holds a Canada Research Chair in Molecular Biology of the Cell Nucleus. We thank Ed Lopata and Lisa McCoy for supporting our research on KMT2A-R leukemia in honor of their son Jesse.

Funding

CAF, LSW, J.S.B., CLW, MD, and SPH supported by Leukemia & Lymphoma Society SCOR 7372-07. CAF supported by ASH Bridge Funding Program, CHOP Bridge Funding Program, Eagles Fly for Leukemia, and CHOP Hematologic Malignancies Research Fund. C.A.F. and S.K.T. supported by SU2C St. Baldrick’s Pediatric Dream Team Translational Research Grant SU2C-AACR-DT1113 (SU2C is a program of Entertainment Industry Foundation administered by AACR). CAF and DTT supported by Cookies for Kids’ Cancer Foundation. SKT supported by K08CA184418 and Rally Foundation for Childhood Cancer Research and was ALSF Scholar in Developmental Therapeutics. AES supported by ACS MRSG-12-215-01-LIB and Hyundai Hope on Wheels Scholar Award. MPC supported by R01CA198089. KLBB funded by R01CA098571 and R01CA080728 and holds a Canada Research Chair. Other support provided by U10CA98413 (COG Statistical Center), U24CA114766 (COG Specimen Banking).

Author information

Author notes

    • Karen A. Urtishak

    Present address: NewAgeSys, Inc., Princeton Junction, NJ, USA

    • Patrizia Porazzi

    Present address: Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA

    • Jeffrey S. Barrett

    Present address: Bill & Melinda Gates Medical Research Institute, Cambridge, MA, USA

    • Blaine W. Robinson

    Present address: Therapy Acceleration Program, Leukemia & Lymphoma Society, Rye Brook, NY, USA

  1. These authors contributed equally: Karen A. Urtishak, Li-San Wang, Biljana Culjkovic-Kraljacic (co-first authors).

Affiliations

  1. Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Karen A. Urtishak
    • , James W. Davenport
    • , Patrizia Porazzi
    • , Tiffaney L. Vincent
    • , David T. Teachey
    • , Sarah K. Tasian
    • , Alix E. Seif
    • , Blaine W. Robinson
    • , Stephen P. Hunger
    •  & Carolyn A. Felix
  2. Department of Pathology and Laboratory Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    • Li-San Wang
    •  & Jonni S. Moore
  3. Institute of Research in Immunology and Cancer (IRIC), Department of Pathology and Cell Biology, Universite de Montreal, Montreal, QC, Canada

    • Biljana Culjkovic-Kraljacic
    •  & Katherine L. B. Borden
  4. Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    • David T. Teachey
    • , Sarah K. Tasian
    • , Alix E. Seif
    • , Jeffrey S. Barrett
    • , Stephen P. Hunger
    •  & Carolyn A. Felix
  5. Division of Hematology and Oncology, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA, USA

    • Shenghao Jin
    •  & Martin P. Carroll
  6. Division of Clinical Pharmacology & Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Jeffrey S. Barrett
  7. Department of Pathology and UNM Cancer Center, University of New Mexico Health Services, Albuquerque, NM, USA

    • I-Ming L. Chen
    • , Richard C. Harvey
    •  & Cheryl L. Willman
  8. Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    • Andrew J. Carroll
  9. Department of Pathology, Ohio State University, Columbus, OH, USA

    • Nyla A. Heerema
  10. Children’s Oncology Group, Department of Biostatistics, Gainesville, FL, USA

    • Meenakshi Devidas
  11. Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA

    • ZoAnn E. Dreyer
  12. Children’s Hospital Colorado and The University of Colorado School of Medicine, Aurora, CO, USA

    • Joanne M. Hilden

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Conflict of interest

CAF owns an unlicensed patent relevant to genetic classification of leukemia cases: Methods and Kits for Analysis of Chromosomal Rearrangements Associated with Leukemia. United States of America 6,368,791. 9 April 2002. CAF owns unlicensed, unrelated patents: United States of America Patent Numbers 6,174,684; and 8,642,265 B2. CAF and LSW submitted an unrelated patent application: United States of America Patent Application 61/490,975. The remaining authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Carolyn A. Felix.

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DOI

https://doi.org/10.1038/s41388-018-0567-7