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

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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.

Original languageEnglish
Article number108200
JournalCell Reports
Volume32
Issue number13
DOIs
Publication statusPublished - 29-09-2020
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General Biochemistry,Genetics and Molecular Biology

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