Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia

• Published in: Leukemia Vol. 32; no. 4; pp. 855 - 864
• Main Authors: Fujita, S, Honma, D, Adachi, N, Araki, K, Takamatsu, E, Katsumoto, T, Yamagata, K, Akashi, K, Aoyama, K, Iwama, A, Kitabayashi, I
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.04.2018; Nature Publishing Group
• Subjects: 13/31; 13/51; 38/91; 45/77; 631/532/71; 631/67/1990/283/1897; 64/60; 82/1; Acute myelocytic leukemia; Acute myeloid leukemia; Analysis; Animal models; Animals; Cancer; Cancer Research; Care and treatment; Catalysis; Catalytic subunits; Cell cycle; Chemotherapy; Clonal deletion; Critical Care Medicine; Cyclin D; Deactivation; Drug resistance; Enhancer of Zeste Homolog 2 Protein - antagonists & inhibitors; Gene expression; Genetic aspects; Hematology; Histone H3; Histones - metabolism; Humans; Inactivation; Inhibition; Inhibitors; Intensive; Internal Medicine; Leukemia; Leukemia, Myeloid, Acute - metabolism; Lysine; Medicine; Medicine & Public Health; Mice; Mice, Inbred C57BL; Myeloid leukemia; Neoplastic Stem Cells - metabolism; Oncology; original-article; Polycomb group proteins; Polycomb Repressive Complex 2 - antagonists & inhibitors; Stem cell transplantation; Stem cells; Xenografts; Xenotransplantation
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.300

Acute myeloid leukemia (AML) is an aggressive and lethal blood cancer originating from rare populations of leukemia stem cells (LSCs). AML relapse after conventional chemotherapy is caused by a remaining population of drug-resistant LSCs. Selective targeting of the chemoresistant population is a promising strategy for preventing and treating AML relapse. Polycomb repressive complex 2 (PRC2) trimethylates histone H3 at lysine 27 to maintain the stemness of LSCs. Here, we show that quiescent LSCs expressed the highest levels of enhancer of zeste (EZH) 1 and EZH2, the PRC2 catalytic subunits, in the AML hierarchy, and that dual inactivation of EZH1/2 eradicated quiescent LSCs to cure AML. Genetic deletion of Ezh1/2 in a mouse AML model induced cell cycle progression of quiescent LSCs and differentiation to LSCs, eventually eradicating AML LSCs. Quiescent LSCs showed PRC2-mediated suppression of Cyclin D , and Cyclin D-overexpressing AML was more sensitive to chemotherapy. We have developed a novel EZH1/2 dual inhibitor with potent inhibitory activity against both EZH1/2. In AML mouse models and patient-derived xenograft models, the inhibitor reduced the number of LSCs, impaired leukemia progression, and prolonged survival. Taken together, these results show that dual inhibition of EZH1/2 is an effective strategy for eliminating AML LSCs.