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Antitumor immunity augments the therapeutic effects of p53 activation on acute myeloid leukemia
- Source :
- Nature Communications, Vol 10, Iss 1, Pp 1-14 (2019), Nature Communications
- Publication Year :
- 2019
- Publisher :
- Nature Portfolio, 2019.
-
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.<br />MDM2 is frequently overexpressed in acute myeloid leukaemia leading to p53 inactivation. Here, the authors are demonstrating that an inhibitor of p53-MDM2 interaction, DS-5272, induce in vivo tumour regression through immune response regulation.
- Subjects :
- 0301 basic medicine
Myeloid
medicine.medical_treatment
General Physics and Astronomy
Cancer immunotherapy
Mice, SCID
B7-H1 Antigen
Mice
0302 clinical medicine
Mice, Inbred NOD
hemic and lymphatic diseases
lcsh:Science
Mice, Knockout
Multidisciplinary
biology
Imidazoles
Myeloid leukemia
Proto-Oncogene Proteins c-mdm2
3. Good health
Killer Cells, Natural
Leukemia
Leukemia, Myeloid, Acute
medicine.anatomical_structure
030220 oncology & carcinogenesis
Mdm2
Immunotherapy
medicine.symptom
Science
Inflammation
General Biochemistry, Genetics and Molecular Biology
Article
Acute myeloid leukaemia
03 medical and health sciences
Immune system
Immunity
medicine
Animals
Humans
neoplasms
business.industry
General Chemistry
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Thiazoles
enzymes and coenzymes (carbohydrates)
030104 developmental biology
Cancer research
biology.protein
lcsh:Q
Tumor Suppressor Protein p53
business
Neoplasm Transplantation
Subjects
Details
- Language :
- English
- ISSN :
- 20411723
- Volume :
- 10
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....fe8d38a94a11f46897e80c6dfe9491e1