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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen / drug effects*
  • B7-H1 Antigen / immunology
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / drug effects*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / immunology
  • Imidazoles / pharmacology*
  • Immunotherapy
  • Inflammation
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / immunology*
  • Leukemia, Myeloid, Acute / immunology*
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplasm Transplantation
  • Proto-Oncogene Proteins c-mdm2 / drug effects*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Thiazoles / pharmacology*
  • Tumor Suppressor Protein p53 / drug effects*
  • Tumor Suppressor Protein p53 / metabolism


  • B7-H1 Antigen
  • Cd274 protein, mouse
  • DS-5272
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Imidazoles
  • Thiazoles
  • Trp53 protein, mouse
  • Tumor Suppressor Protein p53
  • Mdm2 protein, mouse
  • Proto-Oncogene Proteins c-mdm2