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Zebrafish screen identifies novel compound with selective toxicity against leukemia

Ridges, Suzanne and Heaton, Will L. and Joshi, Deepa and Choi, Henry and Eiring, Anna and Batchelor, Lance and Choudhry, Priya and Manos, Elizabeth J. and Sofla, Hossein and Sanati, Ali and Welborn, Seth and Agarwal, Archana and Spangrude, Gerald J. and Miles, Rodney R. and Cox, James E. and Frazer, J. Kimble and Deininger, Michael and Balan, Kaveri and Sigman, Matthew and Müschen, Markus and Perova, Tatiana and Johnson, Radia and Montpellier, Bertrand and Guidos, Cynthia J. and Jones, David A. and Trede, Nikolaus-S (2012) Zebrafish screen identifies novel compound with selective toxicity against leukemia. Blood, 119 (24). pp. 5621-5631. ISSN 0006-4971. PMCID PMC3382926. https://resolver.caltech.edu/CaltechAUTHORS:20140416-132704999

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1182/blood-2011-12-398818DOIArticle
http://bloodjournal.hematologylibrary.org/content/119/24/5621.longPublisherArticle
http://bloodjournal.hematologylibrary.org/content/119/24/5621/suppl/DC1PublisherSupplemental material
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3382926/PubMed CentralArticle
Contact Email Address:docpriya@caltech.edu
Additional Information:Copyright © 2012 by American Society of Hematology. Submitted: December 19, 2011. Accepted: March 11, 2012. The authors wish to acknowledge Ira Kraft, Jon Beck, Rupeng Zhuo, Kalavathy Ramachandran, and Bradley Demarest for expert technical assistance. Histology and immunohistochemistry were performed at the ARUP Institute for Clinical and Experimental Pathology with the technical assistance of Sheryl Tripp. Cell lines and fish strains were a kind gift of Joshua Schiffman, Randy Jensen, and Doug Grossman (University of Utah, Salt Lake City, UT); Adolfo Ferrando (Columbia University, New York, NY); and Andrew Kung, Alejandro Gutierrez, and Thomas Look (Dana- Farber Cancer Institute, Boston, MA). Dr Steven Grant (Virginia Commonwealth University Medical Center, Richmond, VA) provided the myr-AKT plasmid. N.S.T. was supported by The Dana Foundation, The William Lawrence-Blanche Hughes Foundation, The Alex's Lemonade Stand Foundation, and the Huntsman Cancer Foundation. C.J.G. was supported by a grant from Genome Canada Competition III through the Ontario Genomics Institute. Core facilities of the Huntsman Cancer Institute, supported by National Cancer Institute grant P30 CA042014, and the University of Utah, supporting the CZAR zebrafish research core facility, also contributed to this work. S.R., W.L.H., and D.J. contributed equally to this work. The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.
Funders:
Funding AgencyGrant Number
Dana FoundationUNSPECIFIED
William Lawrence-Blanche Hughes FoundationUNSPECIFIED
Alex's Lemonade Stand FoundationUNSPECIFIED
Huntsman Cancer FoundationUNSPECIFIED
Genome Canada Competition IIIUNSPECIFIED
National Cancer InstituteP30 CA042014
University of UtahUNSPECIFIED
Issue or Number:24
PubMed Central ID:PMC3382926
Record Number:CaltechAUTHORS:20140416-132704999
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20140416-132704999
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:44984
Collection:CaltechAUTHORS
Deposited By: SWORD User
Deposited On:21 Apr 2014 23:31
Last Modified:03 Oct 2019 06:25

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