Subject terms
AML, cancers, myelofibrosis
CANCERS, ACUTE MYELOID LEUKEMIA, AML, MYELOFIBROSIS, MUTANT, MYELODYSPLASTIC SYNDROMES
Telomerase enables replicative immortality in most cancers including acute myeloid leukemia (AML). Imetelstat is a first-in-class telomerase inhibitor with clinical efficacy in myelofibrosis and myelodysplastic syndromes. Here, we develop an AML patient-derived xenograft resource and perform integrated genomics, transcriptomics and lipidomics analyses combined with functional genetics to identify key mediators of imetelstat efficacy. In a randomized phase II-like preclinical trial in patient-derived xenografts, imetelstat effectively diminishes AML burden and preferentially targets subgroups containing mutant Bruedigam et al. explore the mechanism of action and therapeutic benefit of telomerase inhibitor imetelstat in a collection of PDXs from patients with AML and demonstrate that, in combination with chemotherapy, it re-sensitizes treatment-resistant AML cells.