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

Yasutaka Hayashi, Susumu Goyama (), XiaoXiao Liu, Moe Tamura, Shuhei Asada, Yosuke Tanaka, Tomofusa Fukuyama, Mark Wunderlich, Eric O’Brien, Benjamin Mizukawa, Satoshi Yamazaki, Akiko Matsumoto, Satoshi Yamasaki, Tatsuhiro Shibata, Koichi Matsuda, Goro Sashida, Hitoshi Takizawa and Toshio Kitamura ()
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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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-12555-1

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