Zebrafish screen identifies novel compound with selective toxicity against leukemia

Ridges, S., Heaton, W.L., Joshi, D., Choi, H., Eiring, A., Batchelor, L., Choudhry, P., Manos, E.J, Sofla, H., Sanati, A., Welborn, S., Agarwal, A., Spangrude, G.J., Miles, R.R., Cox, J.E., Frazer, J.K., Deininger, M., Balan, K., Sigman, M., Müschen, M., Perova, T., Johnson, R., Montpellier, B., Guidos, C.J., Jones, D.A., and Trede, N.S.
Blood   119(24): 5621-5631 (Journal)
Registered Authors
Batchelor, Lance, Frazer, Kimble, Trede, Nick
MeSH Terms
  • Animals
  • Antineoplastic Agents/chemistry
  • Antineoplastic Agents/pharmacokinetics
  • Antineoplastic Agents/therapeutic use
  • Antineoplastic Agents/toxicity*
  • Apoptosis/drug effects
  • Blast Crisis/pathology
  • Cell Differentiation/drug effects
  • Disease Models, Animal
  • Disease Progression
  • Humans
  • Hydrazones/chemistry
  • Hydrazones/pharmacokinetics
  • Hydrazones/therapeutic use
  • Hydrazones/toxicity*
  • Leukemia/drug therapy
  • Leukemia/pathology*
  • Mice
  • Mitosis/drug effects
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors
  • Phosphatidylinositol 3-Kinases/metabolism
  • Phosphorylation/drug effects
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/pathology
  • Proto-Oncogene Proteins c-akt/antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt/metabolism
  • Quinolines/chemistry
  • Quinolines/pharmacokinetics
  • Quinolines/therapeutic use
  • Quinolines/toxicity*
  • Signal Transduction/drug effects
  • T-Lymphocytes/drug effects
  • TOR Serine-Threonine Kinases/antagonists & inhibitors
  • TOR Serine-Threonine Kinases/metabolism
  • Xenograft Model Antitumor Assays
  • Zebrafish/metabolism*
22490804 Full text @ Blood

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.

Genes / Markers
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Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes