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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Proto-Oncogene Proteins c-myb
  • Zebrafish Proteins
  • Tretinoin