High-throughput drug screening of triple combinations in pediatric acute myeloid leukemia

Pediatric AML is genetically and morphologically heterogeneous. Although intensive chemotherapy has improved outcomes, high-risk patients remain vulnerable to relapse and face significant toxicities. While targeted combination therapies may enhance both prognosis and safety, large-scale discovery of synergistic treatments is challenging. We propose a surrogate multiplex drug screening approach using RNA-targeting CRISPR-Cas13. After validating Cas13d stability and guide efficiency via a prescreen of over 300 drug targets, we concurrently target triple drug–gene interactions by silencing relevant mRNAs, enabling identification of synergistic target combinations. A three-step screening in AML cell lines precedes in vivo testing in preclinical AML PDX models and subsequent validation with small-molecule inhibitors. This system will yield new insights into pediatric AML heterogeneity and illuminate potential synergistic therapeutic vulnerabilities.

Publikationsverlauf

Artikel online veröffentlicht:
09. Mai 2025