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Nat Commun. 2019 Oct 25;10(1):4869. doi: 10.1038/s41467-019-12555-1.

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

Author information

1
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
2
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. goyama@ims.u-tokyo.ac.jp.
3
Cancer & Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
4
Division of Stem Cell Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
5
Laboratory of Molecular Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
6
Laboratory of Clinical Genome Sequencing, Department of Computational biology and medical Sciences, Graduate school of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
7
Laboratory of Transcriptional Regulation in Leukemogenesis, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
8
Laboratory of Stem Cell Stress, International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
9
Division of Cellular Therapy, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan. kitamura@ims.u-tokyo.ac.jp.

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.

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