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Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia

Author

Listed:
  • Yasutaka Hayashi

    (The University of Tokyo)

  • Susumu Goyama

    (The University of Tokyo)

  • XiaoXiao Liu

    (The University of Tokyo)

  • Moe Tamura

    (The University of Tokyo)

  • Shuhei Asada

    (The University of Tokyo)

  • Yosuke Tanaka

    (The University of Tokyo)

  • Tomofusa Fukuyama

    (The University of Tokyo)

  • Mark Wunderlich

    (University of Cincinnati College of Medicine)

  • Eric O’Brien

    (University of Cincinnati College of Medicine)

  • Benjamin Mizukawa

    (University of Cincinnati College of Medicine)

  • Satoshi Yamazaki

    (The University of Tokyo)

  • Akiko Matsumoto

    (The University of Tokyo)

  • Satoshi Yamasaki

    (The University of Tokyo)

  • Tatsuhiro Shibata

    (The University of Tokyo)

  • Koichi Matsuda

    (The University of Tokyo)

  • Goro Sashida

    (Kumamoto University)

  • Hitoshi Takizawa

    (Kumamoto University)

  • Toshio Kitamura

    (The University of Tokyo)

Abstract

The negative regulator of p53, MDM2, is frequently overexpressed in acute myeloid leukemia (AML) that retains wild-type TP53 alleles. Targeting of p53-MDM2 interaction to reactivate p53 function is therefore an attractive therapeutic approach for AML. Here we show that an orally active inhibitor of p53-MDM2 interaction, DS-5272, causes dramatic tumor regressions of MLL-AF9-driven AML in vivo with a tolerable toxicity. However, the antileukemia effect of DS-5272 is markedly attenuated in immunodeficient mice, indicating the critical impact of systemic immune responses that drive p53-mediated leukemia suppression. In relation to this, DS-5272 triggers immune-inflammatory responses in MLL-AF9 cells including upregulation of Hif1α and PD-L1, and inhibition of the Hif1α-PD-L1 axis sensitizes AML cells to p53 activation. We also found that NK cells are important mediators of antileukemia immunity. Our study showed the potent activity of a p53-activating drug against AML, which is further augmented by antitumor immunity.

Suggested Citation

  • Yasutaka Hayashi & Susumu Goyama & XiaoXiao Liu & Moe Tamura & Shuhei Asada & Yosuke Tanaka & Tomofusa Fukuyama & Mark Wunderlich & Eric O’Brien & Benjamin Mizukawa & Satoshi Yamazaki & Akiko Matsumot, 2019. "Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12555-1
    DOI: 10.1038/s41467-019-12555-1
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    Cited by:

    1. Ruiqing Wang & Xinyu Yang & Jinting Liu & Fang Zhong & Chen Zhang & Yuhong Chen & Tao Sun & Chunyan Ji & Daoxin Ma, 2022. "Gut microbiota regulates acute myeloid leukaemia via alteration of intestinal barrier function mediated by butyrate," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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