Inhibition of PLK4 remodels histone methylation and activates the immune response via the cGAS-STING pathway in TP53-mutated AML

Author:

Man Cheuk-Him1,Lam Wing1,Dang Chee-Chean1,Zeng Xiao-yuan1,Zheng Li-Chuan1,Chan Natalie Nok-Man1,Ng Ka-Lam1,Chan Koon-Chuen1,Kwok Tsz-Ho1,Ng Timothy Chi-Chun1,Leung Wing-Yan1,Huen Michael Shing-Yan2,Wong Carmen Chak-Lui345,So Chi Wai Eric6ORCID,Dou Zhixun78,Goyama Susumu9ORCID,Bray Mark Robert10,Mak Tak Wah3510,Leung Anskar Yu-Hung15

Affiliation:

1. 1Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

2. 2School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China

3. 3Department of Pathology, The University of Hong Kong, Hong Kong SAR, China

4. 4State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China

5. 5Centre for Oncology and Immunology, Hong Kong Science Park, Hong Kong SAR, China

6. 6Department of Haematological Medicine, Leukemia and Stem Cell Biology Team, King's College London, London, UK

7. 7Center for Regenerative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA

8. 8Harvard Stem Cell Institute, Harvard University, Cambridge, MA

9. 9Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan

10. 10The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, Toronto, Canada

Abstract

Abstract Acute myeloid leukemia (AML) with TP53 mutation is one of the most lethal cancers and portends an extremely poor prognosis. Based on in silico analyses of druggable genes and differential gene expression in TP53-mutated AML, we identified pololike kinase 4 (PLK4) as a novel therapeutic target and examined its expression, regulation, pathogenetic mechanisms, and therapeutic potential in TP53-mutated AML. PLK4 expression was suppressed by activated p53 signaling in TP53 wild-type AML and was increased in TP53-mutated AML cell lines and primary samples. Short-term PLK4 inhibition induced DNA damage and apoptosis in TP53 wild-type AML. Prolonged PLK4 inhibition suppressed the growth of TP53-mutated AML and was associated with DNA damage, apoptosis, senescence, polyploidy, and defective cytokinesis. A hitherto undescribed PLK4/PRMT5/EZH2/H3K27me3 axis was demonstrated in both TP53 wild-type and mutated AML, resulting in histone modification through PLK4-induced PRMT5 phosphorylation. In TP53-mutated AML, combined effects of histone modification and polyploidy activated the cGAS-STING pathway, leading to secretion of cytokines and chemokines and activation of macrophages and T cells upon coculture with AML cells. In vivo, PLK4 inhibition also induced cytokine and chemokine expression in mouse recipients, and its combination with anti-CD47 antibody, which inhibited the “don’t-eat-me” signal in macrophages, synergistically reduced leukemic burden and prolonged animal survival. The study shed important light on the pathogenetic role of PLK4 and might lead to novel therapeutic strategies in TP53-mutated AML.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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