Blood Journal
Leading the way in experimental and clinical research in hematology

Zebrafish screen identifies novel compound with selective toxicity against leukemia

  1. Suzanne Ridges1,
  2. Will L. Heaton1,
  3. Deepa Joshi1,
  4. Henry Choi1,
  5. Anna Eiring1,
  6. Lance Batchelor1,
  7. Priya Choudhry1,
  8. Elizabeth J. Manos1,
  9. Hossein Sofla1,
  10. Ali Sanati1,
  11. Seth Welborn1,
  12. Archana Agarwal2,
  13. Gerald J. Spangrude2,
  14. Rodney R. Miles2,
  15. James E. Cox3,
  16. J. Kimble Frazer4,
  17. Michael Deininger5,
  18. Kaveri Balan6,
  19. Matthew Sigman6,
  20. Markus Müschen7,
  21. Tatiana Perova8,
  22. Radia Johnson8,
  23. Bertrand Montpellier8,
  24. Cynthia J. Guidos9,
  25. David A. Jones1, and
  26. Nikolaus S. Trede1,*
  1. 1 Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, United States;
  2. 2 Department of Pathology, University of Utah, Salt Lake City, UT, United States;
  3. 3 Metabolomics Core Facility, University of Utah, Salt Lake City, UT, United States;
  4. 4 Department of Pediatrics, University of Utah, Salt Lake City, UT, United States;
  5. 5 Department of Hematology, University of Utah, Salt Lake City, UT, United States;
  6. 6 Department of Chemistry, University of Utah, Salt Lake City, UT, United States;
  7. 7 Leukemia and Lymphoma Program, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, United States;
  8. 8 Program in Developmental and Stem Cell Biology, Hospital for Sick Children Research Institute, University of Toronto, Toronto, ON, Canada;
  9. 9 Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
  1. * Corresponding author; email: nikolaus.trede{at}hci.utah.edu

Abstract

To detect targeted anti-leukemia agents we have designed a novel, high-content in vivo screen using genetically engineered, T cell-reporting zebrafish. We exploited the developmental similarities between normal and malignant T lymphoblasts to screen a small molecule library for activity against immature T cells with a simple visual read-out in zebrafish larvae. After screening 26,400 molecules, we identified Lenaldekar (LDK), a compound that eliminates immature T cells in developing zebrafish without affecting the cell cycle in other cell types. LDK is well tolerated in vertebrates and induces long-term remission in adult zebrafish with cMYC-induced T cell acute lymphoblastic leukemia (T-ALL). LDK causes dephosphorylation of members of the PI3 kinase/AKT/mTOR pathway and delays sensitive cells in late mitosis. Among human cancers, LDK selectively affects survival of hematopoietic malignancy lines and primary leukemias, including therapy-refractory B-ALL and CML samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for anti-neoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. While our efforts focused on leukemia therapy, this screening approach has broad implications as it can be translated to other cancer types involving malignant degeneration of developmentally arrested cells.

  • Submitted December 19, 2011.
  • Accepted March 11, 2012.