PUBLICATION

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

Authors
Mandelbaum, J., Shestopalov, I.A., Henderson, R.E., Chau, N.G., Knoechel, B., Wick, M.J., Zon, L.I.
ID
ZDB-PUB-180914-4
Date
2018
Source
The Journal of experimental medicine   215(10): 2673-2685 (Journal)
Registered Authors
Shestopalov, Ilya, Zon, Leonard I.
Keywords
none
MeSH Terms
  • Animals
  • Blastomeres/immunology*
  • Blastomeres/pathology
  • Carcinoma, Adenoid Cystic/drug therapy*
  • Carcinoma, Adenoid Cystic/genetics
  • Carcinoma, Adenoid Cystic/immunology
  • Carcinoma, Adenoid Cystic/pathology
  • Humans
  • Mice
  • Mice, Nude
  • Proto-Oncogene Proteins c-myb/antagonists & inhibitors*
  • Proto-Oncogene Proteins c-myb/genetics
  • Proto-Oncogene Proteins c-myb/immunology
  • Salivary Gland Neoplasms/drug therapy*
  • Salivary Gland Neoplasms/genetics
  • Salivary Gland Neoplasms/immunology
  • Salivary Gland Neoplasms/pathology
  • Tretinoin/pharmacology*
  • U937 Cells
  • Xenograft Model Antitumor Assays
  • Zebrafish/genetics
  • Zebrafish/immunology*
  • Zebrafish Proteins/antagonists & inhibitors*
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/immunology
PubMed
30209067 Full text @ J. Exp. Med.
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.
Genes / Markers
Figures
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping