Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia

Ryo Miyamoto; Hiroshi Okuda; Akinori Kanai; Satoshi Takahashi; Takeshi Kawamura; Hirotaka Matsui; Toshio Kitamura; Issay Kitabayashi; Toshiya Inaba; Akihiko Yokoyama

doi:10.1016/j.celrep.2020.108200

Activation of CpG-Rich Promoters Mediated by MLL Drives MOZ-Rearranged Leukemia

Cell Rep. 2020 Sep 29;32(13):108200. doi: 10.1016/j.celrep.2020.108200.

Authors

Affiliations

¹ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan.
² Department of Molecular Oncology and Leukemia Program Project, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
³ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Department of Hematology and Oncology, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
⁴ Isotope Science Center, The University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
⁵ Department of Molecular Laboratory Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁶ Division of Cellular Therapy and Division of Stem Cell Signaling, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
⁷ Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
⁸ Tsuruoka Metabolomics Laboratory, National Cancer Center, Tsuruoka, Yamagata 997-0052, Japan; Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan. Electronic address: ayokoyam@ncc-tmc.jp.

PMID: 32997997
DOI: 10.1016/j.celrep.2020.108200

Abstract

Uncontrolled self-renewal of hematopoietic progenitors induces leukemia. To self-renew, leukemia cells must continuously activate genes that were previously active in their mother cells. Here, we describe the circuitry of a transactivation system responsible for oncogenic self-renewal. MLL recruits RNA polymerase II (RNAP2) to unmethylated CpG-rich promoters by its CXXC domain and activates transcription by transcriptional regulators, including the AF4 family/ENL family/P-TEFb complex, DOT1L, and p300/CBP histone acetyl transferases. MOZ also targets a broad range of CpG-rich promoters through association with RNAP2 and MLL. Leukemic fusion proteins such as MOZ-TIF2 and MLL-AFX constitutively activate CpG-rich promoters by aberrantly recruiting p300/CBP. Pharmacological inhibition of MLL or DOT1L induces differentiation of MOZ-TIF2-transformed cells. These results reveal that activation of unmethylated CpG-rich promoters mediated by MLL is the central mechanism of oncogenic self-renewal in MOZ-rearranged leukemia and indicate that the molecularly targeted therapies intended for MLL-rearranged leukemia can be applied for MOZ-rearranged leukemia.

Keywords: CXXC domain; ENL; MLL; MOZ; RNA polymerase II; histone acetyl transferase; leukemia; self-renewal; transcription; unmethylated CpG.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
CpG Islands / genetics*
Humans
Mice
Mutation
Myeloid-Lymphoid Leukemia Protein / genetics*
Myeloid-Lymphoid Leukemia Protein / metabolism
Oncogene Proteins, Fusion / metabolism*

Substances

Oncogene Proteins, Fusion
Myeloid-Lymphoid Leukemia Protein