Zebrafish blastomere screen identifies retinoic acid suppression of

Area of Science:

• Developmental biology
• Cancer research
• Pharmacology

Background:

• Pluripotent cells are crucial for studying developmental pathways in genetic diseases and cancer.
• MYB-driven tumors, including adenoid cystic carcinoma (ACC), lack effective targeted therapies.
• Identifying novel therapeutic targets for MYB-driven malignancies is a significant unmet need.

Purpose of the Study:

• To develop a pluripotent zebrafish blastomere culture system for identifying new therapies against MYB-driven tumors.
• To investigate the potential of retinoic acid as a therapeutic agent for ACC.

Main Methods:

• A chemical genetic screen was performed using a pluripotent zebrafish blastomere culture system.
• Retinoic acid agonists were tested for their ability to suppress c-myb expression.
• In vivo efficacy was assessed in patient-derived xenograft models of ACC.

Main Results:

• Retinoic acid agonists were identified as suppressors of c-myb expression in the zebrafish system.
• Retinoic acid treatment reduced c-myb gene expression in human leukemia cells.
• Retinoic acid agonists inhibited tumor growth in ACC xenografts and reduced MYB binding at enhancers, disrupting the MYB positive feedback loop.

Conclusions:

• The zebrafish pluripotent cell culture system is effective for identifying modulators of tumor formation.
• Retinoic acid demonstrates significant potential as a novel therapeutic strategy for adenoid cystic carcinoma.
• Targeting the MYB feedback loop with retinoic acid offers a promising avenue for ACC treatment.