Zebrafish screen identifies novel compound with selective toxicity against leukemia

Area of Science:

• Biomedical research
• Zebrafish models
• Drug discovery

Background:

• T-cell acute lymphoblastic leukemia (T-ALL) is a significant challenge in pediatric oncology.
• Developing novel therapeutic agents for refractory leukemia remains critical.
• Zebrafish offer a powerful platform for high-content in vivo screening.

Purpose of the Study:

• To establish a novel high-content in vivo screen for identifying targeted antileukemia agents.
• To discover compounds effective against immature T cells using a zebrafish model.
• To investigate the therapeutic potential of identified compounds in T-ALL.

Main Methods:

• Genetically engineered, T-cell reporting zebrafish were utilized for in vivo screening.
• A small molecule library of 26,400 compounds was screened for activity against immature T cells.
• The compound Lenaldekar (LDK) was identified and its effects on zebrafish and human cancer models were analyzed.

Main Results:

• Lenaldekar (LDK) selectively eliminated immature T cells in zebrafish larvae without impacting other cell types.
• LDK demonstrated efficacy in inducing long-term remission in adult zebrafish with cMYC-induced T-ALL.
• LDK showed selective effects on hematopoietic malignancy cell lines and primary leukemias, including therapy-refractory cases, and inhibited human T-ALL xenografts.

Conclusions:

• The developed zebrafish screening method is effective for identifying antineoplastic drug candidates.
• Lenaldekar (LDK) represents a promising new therapeutic approach for targeted leukemia therapy.
• The screening approach has broad implications for identifying treatments for other cancers involving developmentally arrested malignant cells.