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J Exp Med. 2018 Oct 1;215(10):2673-2685. doi: 10.1084/jem.20180939. Epub 2018 Sep 12.

Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma.

Author information

1
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
3
Broad Institute of MIT and Harvard, Harvard Medical School, Boston, MA.
4
South Texas Accelerated Research Therapeutics, San Antonio, TX.
5
Stem Cell Program and Division of Hematology/Oncology, Boston Children's Hospital and Dana-Farber Cancer Institute, Howard Hughes Medical Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA zon@enders.tch.harvard.edu.

Abstract

Pluripotent cells have been used to probe developmental pathways that are involved in genetic diseases and oncogenic events. To find new therapies that would target MYB-driven tumors, we developed a pluripotent zebrafish blastomere culture system. We performed a chemical genetic screen and identified retinoic acid agonists as suppressors of c-myb expression. Retinoic acid treatment also decreased c-myb gene expression in human leukemia cells. Translocations that drive overexpression of the oncogenic transcription factor MYB are molecular hallmarks of adenoid cystic carcinoma (ACC), a malignant salivary gland tumor with no effective therapy. Retinoic acid agonists inhibited tumor growth in vivo in ACC patient-derived xenograft models and decreased MYB binding at translocated enhancers, thereby potentially diminishing the MYB positive feedback loop driving ACC. Our findings establish the zebrafish pluripotent cell culture system as a method to identify modulators of tumor formation, particularly establishing retinoic acid as a potential new effective therapy for ACC.

PMID:
30209067
PMCID:
PMC6170170
[Available on 2019-04-01]
DOI:
10.1084/jem.20180939

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