Main
blood cancer, AML
BLOOD CANCER, DISEASE, AML, LEUKEMIA STEM CELL
AML is an aggressive and lethal blood cancer with a 5-year overall survival rate of less than 45% for patients younger than 60 years of age and less than 10% for older patients, predominantly due to disease relapse after chemotherapy or targeted treatments. AML has been extensively classified based on biological features and advances in sequencing technologies have led to a comprehensive genetic classification strategy (European LeukemiaNet, ELN2017)Telomerase is an attractive target as it is highly expressed and reactivated in the majority of AML and absent in most cell types including healthy hematopoietic cells. We have previously shown that genetic depletion of telomerase eradicates leukemia stem cells, particularly upon enforced replicationIn addition to its canonical role as critical regulator of telomere length maintenance, telomerase fulfills important non-canonical roles contributing to stress elimination, regulation of Wnt/β-catenin, NF-κB and p65 signaling, as well as resistance to ionizing radiationPreclinical trials in patient-derived xenografts (PDXs) provide genetically diverse, tractable models to define the efficacy of drugs and to identify biomarkers of response and resistance in AMLIn this study, we aimed to assess the preclinical efficacy of imetelstat in a large AML PDX resource that reflects the diversity of genetic abnormalities found in large patient cohorts. We utilized this AML PDX resource to identify biomarkers of resistance and response to imetelstat therapy and to test potentially synergistic combination therapies. To elucidate the mechanism of action of imetelstat in an unbiased manner, we performed genome-wide CRISPR/Cas9 editing allowing the identification of gene knockouts that confer resistance to imetelstat therapy. This study reveals that imetelstat is a potent inducer of ferroptosis that effectively diminishes AML burden and delays relapse following oxidative stress-inducing therapy.