Bruedigam Claudia, Bagger Frederik O, Heidel Florian H, Paine Kuhn Catherine, Guignes Solene, Song Axia, Austin Rebecca, Vu Therese, Lee Erwin, Riyat Sarbjit, Moore Andrew S, Lock Richard B, Bullinger Lars, Hill Geoffrey R, Armstrong Scott A, Williams David A, Lane Steven W
Division of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
The Finsen Laboratory, Bioinformatics Centre, Department of Biology, and Biotech Research and Innovation Center (BRIC), University of Copenhagen, 1165 Copenhagen, Denmark.
Cell Stem Cell. 2014 Dec 4;15(6):775-90. doi: 10.1016/j.stem.2014.11.010.
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.
急性髓系白血病（AML）是一种侵袭性致命血液癌症，由罕见的白血病干细胞（LSC）群体维持。选择性靶向LSC是治疗AML和预防化疗后复发的一种有前景的方法，开发此类治疗方式是关键优先事项。在此，我们表明靶向端粒酶活性可根除AML LSC。在逆转录病毒小鼠AML模型中，端粒酶亚基Terc的基因缺失诱导LSC的细胞周期停滞和凋亡，并且p53敲低可部分挽救端粒酶缺陷型LSC的耗竭。小鼠Terc(-/-) LSC表达一种特定的基因表达特征，该特征可在人类AML患者队列中识别，并且与化疗后患者生存呈正相关。在原发性人类AML异种移植中，端粒酶的基因或药理学抑制靶向LSC，损害白血病进展，并延迟化疗后的复发。总之，这些结果确立了端粒酶抑制作为消除AML LSC的有效策略。
