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

S. Fujita, D. Honma, N. Adachi, K. Araki, E. Takamatsu, T. Katsumoto, K. Yamagata, Koichi Akashi, K. Aoyama, A. Iwama, I. Kitabayashi

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)855-864
Number of pages10
JournalLeukemia
Volume32
Issue number4
DOIs
Publication statusPublished - Apr 1 2018

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Acute Myeloid Leukemia
Leukemia
Stem Cells
Polycomb Repressive Complex 2
Cyclin D
Population
Recurrence
Drug Therapy
Heterografts
Histones
Lysine
Cell Differentiation
Catalytic Domain
Cell Cycle
Survival

All Science Journal Classification (ASJC) codes

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Fujita, S., Honma, D., Adachi, N., Araki, K., Takamatsu, E., Katsumoto, T., ... Kitabayashi, I. (2018). Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. Leukemia, 32(4), 855-864. https://doi.org/10.1038/leu.2017.300

Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. / Fujita, S.; Honma, D.; Adachi, N.; Araki, K.; Takamatsu, E.; Katsumoto, T.; Yamagata, K.; Akashi, Koichi; Aoyama, K.; Iwama, A.; Kitabayashi, I.

In: Leukemia, Vol. 32, No. 4, 01.04.2018, p. 855-864.

Research output: Contribution to journalArticle

Fujita, S, Honma, D, Adachi, N, Araki, K, Takamatsu, E, Katsumoto, T, Yamagata, K, Akashi, K, Aoyama, K, Iwama, A & Kitabayashi, I 2018, 'Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia', Leukemia, vol. 32, no. 4, pp. 855-864. https://doi.org/10.1038/leu.2017.300
Fujita S, Honma D, Adachi N, Araki K, Takamatsu E, Katsumoto T et al. Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. Leukemia. 2018 Apr 1;32(4):855-864. https://doi.org/10.1038/leu.2017.300
Fujita, S. ; Honma, D. ; Adachi, N. ; Araki, K. ; Takamatsu, E. ; Katsumoto, T. ; Yamagata, K. ; Akashi, Koichi ; Aoyama, K. ; Iwama, A. ; Kitabayashi, I. / Dual inhibition of EZH1/2 breaks the quiescence of leukemia stem cells in acute myeloid leukemia. In: Leukemia. 2018 ; Vol. 32, No. 4. pp. 855-864.
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