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

Research paper by Yasutaka Y Hayashi, Susumu S Goyama, XiaoXiao X Liu, Moe M Tamura, Shuhei S Asada, Yosuke Y Tanaka, Tomofusa T Fukuyama, Mark M Wunderlich, Eric E O'Brien, Benjamin B Mizukawa, Satoshi S Yamazaki, Akiko A Matsumoto, Satoshi S Yamasaki, Tatsuhiro T Shibata, Koichi K Matsuda, et al.

Indexed on: 29 Oct '19Published on: 28 Oct '19Published in: Nature communications


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.