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

November 20 2019

Hitoshi Takizawa, Goro Sasahida

Paper information
Yasutaka Hayashi¹, Susumu Goyama¹, XiaoXiao Liu¹, Shuhei Asada¹, Yosuke Tanaka¹,Tomofusa Fukuyama¹, Mark Wunderlich², Eric O'Brien², Benjamin Mizukawa²,Satoshi Yamazaki³_, Akiko Matsumoto⁴, Satoshi Yamasaki⁴, Tatsuhiro Shibata⁴,  Koichi Matsuda⁵, Goro Sashida⁶, Hitoshi Takizawa⁶, Toshio Kitamura¹

¹Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
²Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
³Division of Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁴Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁵Laboratory of Genome Technology, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
⁶International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.

Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia
Nat Commun. 2019 Oct 25;10(1):4869. doi: 10.1038/s41467-019-12555-1.

Key words: Acute myeloid leukemia, p53-MDM2 interaction inhibitor, Hif1a, PD-L1, tumor immunity 

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.