2. Academic Validation
  3. Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas

Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas

  • Cell Rep. 2019 Nov 19;29(8):2321-2337.e7. doi: 10.1016/j.celrep.2019.10.083.
Makoto Yamagishi 1,  Makoto Hori 2,  Dai Fujikawa 3,  Takeo Ohsugi 4,  Daisuke Honma 5,  Nobuaki Adachi 6,  Harutaka Katano 7,  Tsunekazu Hishima 8,  Seiichiro Kobayashi 9,  Kazumi Nakano 2,  Makoto Nakashima 2,  Masako Iwanaga 10,  Atae Utsunomiya 11,  Yuetsu Tanaka 12,  Seiji Okada 13,  Kunihiro Tsukasaki 14,  Kensei Tobinai 15,  Kazushi Araki 16,  Toshiki Watanabe 17,  Kaoru Uchimaru 18
Affiliations

Affiliations

  • 1 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: myamagishi@edu.k.u-tokyo.ac.jp.
  • 2 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
  • 3 Animal Models and Retroviral Vaccines Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
  • 4 Department of Laboratory Animal Science, School of Veterinary Medicine, Rakuno Gakuen University, Hokkaido, Japan.
  • 5 Oncology Laboratories, Daiichi Sankyo, Co., Tokyo, Japan.
  • 6 Biomarker Department, Daiichi Sankyo, Co., Tokyo, Japan.
  • 7 Department of Pathology, National Institute of Infectious Diseases, Tokyo, Japan.
  • 8 Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
  • 9 Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 10 Department of Clinical Epidemiology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan.
  • 11 Department of Hematology, Imamura General Hospital, Kagoshima, Japan.
  • 12 Graduate School and Faculty of Medicine, University of the Ryukyus, Okinawa, Japan.
  • 13 Joint Research Center for Human Retrovirus Infection, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
  • 14 Department of Hematology, International Medical Center, Saitama Medical University, Saitama, Japan.
  • 15 Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
  • 16 Oncology Clinical Development Department, Daiichi Sankyo Co., Tokyo, Japan.
  • 17 Future Center Initiative, The University of Tokyo, Tokyo, Japan.
  • 18 Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan. Electronic address: uchimaru@cbms.k.u-tokyo.ac.jp.
PMID: 31747604 DOI: 10.1016/j.celrep.2019.10.083
Abstract

Although global H3K27me3 reprogramming is a hallmark of Cancer, no effective therapeutic strategy for H3K27me3-high malignancies harboring EZH2WT/WT has yet been established. We explore epigenome and transcriptome in EZH2WT/WT and EZH2WT/Mu aggressive lymphomas and show that mutual interference and compensatory function of co-expressed EZH1 and EZH2 rearrange their own genome-wide distribution, thereby establishing restricted chromatin and gene expression signatures. Direct comparison of leading compounds introduces potency and a mechanism of action of the EZH1/2 dual inhibitor (valemetostat). The synthetic lethality is observed in all lymphoma models and primary adult T cell leukemia-lymphoma (ATL) cells. Opposing actions of EZH1/2-polycomb and SWI/SNF complexes are required for facultative heterochromatin formation. Inactivation of chromatin-associated genes (ARID1A, SMARCA4/BRG1, SMARCB1/SNF5, KDM6A/UTX, BAP1, KMT2D/MLL2) and oncovirus Infection (HTLV-1, EBV) trigger EZH1/2 perturbation and H3K27me3 deposition. Our study provides the mechanism-based rationale for chemical dual targeting of EZH1/2 in Cancer epigenome.

Keywords

EZH1; EZH2; H3K27me3; HTLV-1; adult T cell leukemia-lymphoma (ATL); epigenetic drug; malignant lymphoma; polycomb.

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