Zebrafish screen identifies novel compound with selective toxicity against leukemia
- Creators
- Ridges, Suzanne
- Heaton, Will L.
- Joshi, Deepa
- Choi, Henry
- Eiring, Anna
- Batchelor, Lance
- Choudhry, Priya
- Manos, Elizabeth J.
- Sofla, Hossein
- Sanati, Ali
- Welborn, Seth
- Agarwal, Archana
- Spangrude, Gerald J.
- Miles, Rodney R.
- Cox, James E.
- Frazer, J. Kimble
- Deininger, Michael
- Balan, Kaveri
- Sigman, Matthew
- Müschen, Markus
- Perova, Tatiana
- Johnson, Radia
- Montpellier, Bertrand
- Guidos, Cynthia J.
- Jones, David A.
- Trede, Nikolaus-S
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.
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.Attached Files
Published - Blood-2012.pdf
Supplemental Material - blood-2011-12-398818-1.pdf
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Additional details
- PMCID
- PMC3382926
- Eprint ID
- 44984
- Resolver ID
- CaltechAUTHORS:20140416-132704999
- Dana Foundation
- William Lawrence-Blanche Hughes Foundation
- Alex's Lemonade Stand Foundation
- Huntsman Cancer Foundation
- Genome Canada Competition III
- P30 CA042014
- National Cancer Institute
- University of Utah
- Created
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2014-04-21Created from EPrint's datestamp field
- Updated
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2021-11-10Created from EPrint's last_modified field