RRC ID 57694
Author Hayashi Y, Goyama S, Liu X, Tamura M, Asada S, Tanaka Y, Fukuyama T, Wunderlich M, O'Brien E, Mizukawa B, Yamazaki S, Matsumoto A, Yamasaki S, Shibata T, Matsuda K, Sashida G, Takizawa H, Kitamura T.
Title Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia.
Journal Nat Commun
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.
Volume 10(1)
Pages 4869
Published 2019-10-25
DOI 10.1038/s41467-019-12555-1
PII 10.1038/s41467-019-12555-1
PMID 31653912
PMC PMC6814808
MeSH 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
IF 12.121
Times Cited 1
Mice RBRC01361