title: Zebrafish screen identifies novel compound with selective toxicity against leukemia.
abstract: To detect targeted antileukemia 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 readout 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 chronic myelogenous leukemia samples, and inhibits growth of human T-ALL xenografts. This work demonstrates the utility of our method using zebrafish for antineoplastic candidate drug identification and suggests a new approach for targeted leukemia therapy. Although 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.
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Ridges
authors.forename: Will L
authors.initials: WL
authors.lastname: Heaton
authors.forename: Deepa
authors.initials: D
authors.lastname: Joshi
authors.forename: Henry
authors.initials: H
authors.lastname: Choi
authors.forename: Anna
authors.initials: A
authors.lastname: Eiring
authors.forename: Lance
authors.initials: L
authors.lastname: Batchelor
authors.forename: Priya
authors.initials: P
authors.lastname: Choudhry
authors.forename: Elizabeth J
authors.initials: EJ
authors.lastname: Manos
authors.forename: Hossein
authors.initials: H
authors.lastname: Sofla
authors.forename: Ali
authors.initials: A
authors.lastname: Sanati
authors.forename: Seth
authors.initials: S
authors.lastname: Welborn
authors.forename: Archana
authors.initials: A
authors.lastname: Agarwal
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Spangrude
authors.forename: Rodney R
authors.initials: RR
authors.lastname: Miles
authors.forename: James E
authors.initials: JE
authors.lastname: Cox
authors.forename: J Kimble
authors.initials: JK
authors.lastname: Frazer
authors.forename: Michael
authors.initials: M
authors.lastname: Deininger
authors.forename: Kaveri
authors.initials: K
authors.lastname: Balan
authors.forename: Matthew
authors.initials: M
authors.lastname: Sigman
authors.forename: Markus
authors.initials: M
authors.lastname: Müschen
authors.forename: Tatiana
authors.initials: T
authors.lastname: Perova
authors.forename: Radia
authors.initials: R
authors.lastname: Johnson
authors.forename: Bertrand
authors.initials: B
authors.lastname: Montpellier
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Guidos
authors.forename: David A
authors.initials: DA
authors.lastname: Jones
authors.forename: Nikolaus S
authors.initials: NS
authors.lastname: Trede
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D006801:Humans; D006835:Hydrazones / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D007938:Leukemia / Q000188:drug therapy / Q000473:pathology*; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000633:toxicity*; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D006835:Hydrazones; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C571887:1H-indole-3-carbaldehyde quinolin-8-yl-hydrazone