| First Author | Hayashi Y | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 4869 |
| PubMed ID | 31653912 | Mgi Jnum | J:281338 |
| Mgi Id | MGI:6377748 | Doi | 10.1038/s41467-019-12555-1 |
| Citation | Hayashi Y, et al. (2019) Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia. Nat Commun 10(1):4869 |
| abstractText | 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 Hif1alpha and PD-L1, and inhibition of the Hif1alpha-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. |
