Bruedigam, Claudia2; Bagger, Frederik Otzen7; Heidel, Florian H.8; Kuhn, Catherine Paine2; Guignes, Solene2; Song, Axia2; Austin, Rebecca2; Vu, Therese2; Lee, Erwin9; Riyat, Sarbjit5; Moore, Andrew S.6; Lock, Richard B.6; Bullinger, Lars6; Hill, Geoffrey R.6; Armstrong, Scott A.6; Williams, David A.6; Lane, Steven W.6
1 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet2 QIMR Berghofer Medical Research Institute3 Otto-von-Guericke University Magdeburg4 University of New South Wales5 Women’s Hospital, Brisbane6 unknown7 Computational and RNA Biology, Department of Biology, Faculty of Science, Københavns Universitet8 Otto-von-Guericke University Magdeburg9 University of New South Wales
Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer maintained by rare populations of leukemia stem cells (LSCs). Selective targeting of LSCs is a promising approach for treating AML and preventing relapse following chemotherapy, and developing such therapeutic modalities is a key priority. Here, we show that targeting telomerase activity eradicates AML LSCs. Genetic deletion of the telomerase subunit Terc in a retroviral mouse AML model induces cell-cycle arrest and apoptosis of LSCs, and depletion of telomerase-deficient LSCs is partially rescued by p53 knockdown. Murine Terc(-/-) LSCs express a specific gene expression signature that can be identified in human AML patient cohorts and is positively correlated with patient survival following chemotherapy. In xenografts of primary human AML, genetic or pharmacological inhibition of telomerase targets LSCs, impairs leukemia progression, and delays relapse following chemotherapy. Altogether, these results establish telomerase inhibition as an effective strategy for eliminating AML LSCs.