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Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia

Author

Listed:
  • Liping Dou

    (Medical School of Chinese PLA
    University of Minnesota)

  • Fei Yan

    (University of Minnesota
    Jilin University)

  • Jiuxia Pang

    (University of Minnesota)

  • Dehua Zheng

    (Medical School of Chinese PLA)

  • Dandan Li

    (Medical School of Chinese PLA)

  • Li Gao

    (Medical School of Chinese PLA)

  • Lijun Wang

    (University of Minnesota)

  • Yihan Xu

    (Medical School of Chinese PLA)

  • Jinlong Shi

    (Medical School of Chinese PLA)

  • Qian Wang

    (Medical School of Chinese PLA)

  • Lei Zhou

    (Medical School of Chinese PLA)

  • Na Shen

    (University of Minnesota)

  • Puja Singh

    (University of Minnesota)

  • Lili Wang

    (Medical School of Chinese PLA)

  • Yonghui Li

    (Medical School of Chinese PLA)

  • Yvchi Gao

    (Annoroad Gene Technical Laboratory)

  • Tao Liu

    (Annoroad Gene Technical Laboratory)

  • Chongjian Chen

    (Annoroad Gene Technical Laboratory)

  • Aref Al-Kali

    (Mayo Clinic)

  • Mark R. Litzow

    (Mayo Clinic)

  • Young-In Chi

    (University of Minnesota)

  • Ann M. Bode

    (University of Minnesota)

  • Chunhui Liu

    (Haoshi Biotechnical Laboratory)

  • Haojie Huang

    (Mayo Clinic)

  • Daihong Liu

    (Medical School of Chinese PLA)

  • Guido Marcucci

    (City of Hope)

  • Shujun Liu

    (University of Minnesota)

  • Li Yu

    (Shenzhen University General Hospital, Shenzhen University Health Science Center)

Abstract

The oncogenic fusion protein AML1-ETO retains the ability of AML1 to interact with the enhancer core DNA sequences, but blocks AML1-dependent transcription. Previous studies have shown that post-translational modification of AML1-ETO may play a role in its regulation. Here we report that AML1-ETO-positive patients, with high histone lysine methyltransferase Enhancer of zeste homolog 1 (EZH1) expression, show a worse overall survival than those with lower EZH1 expression. EZH1 knockdown impairs survival and proliferation of AML1-ETO-expressing cells in vitro and in vivo. We find that EZH1 WD domain binds to the AML1-ETO NHR1 domain and methylates AML1-ETO at lysine 43 (Lys43). This requires the EZH1 SET domain, which augments AML1-ETO-dependent repression of tumor suppressor genes. Loss of Lys43 methylation by point mutation or domain deletion impairs AML1-ETO-repressive activity. These findings highlight the role of EZH1 in non-histone lysine methylation, indicating that cooperation between AML1-ETO and EZH1 and AML1-ETO site-specific lysine methylation promote AML1-ETO transcriptional repression in leukemia.

Suggested Citation

  • Liping Dou & Fei Yan & Jiuxia Pang & Dehua Zheng & Dandan Li & Li Gao & Lijun Wang & Yihan Xu & Jinlong Shi & Qian Wang & Lei Zhou & Na Shen & Puja Singh & Lili Wang & Yonghui Li & Yvchi Gao & Tao Liu, 2019. "Protein lysine 43 methylation by EZH1 promotes AML1-ETO transcriptional repression in leukemia," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12960-6
    DOI: 10.1038/s41467-019-12960-6
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