Mutant p53 drives clonal hematopoiesis through modulating epigenetic pathway

Sisi Chen,H Scott Boswell,Eric R Wolf,Stephen Z Liu,Zhonghua Gao,Wenjie Cai,Yang Sun,Zhigang Cai,Sasidhar Vemula,Na Luo,Danielle Henley,Hongyu Gao,Rui Gao,Reuben Kapur,Mervin C Yöder ,Yunlong Liu,Terrence N Wong,Aidan Fahey,Chonghua Yao,Baskar Ramdas,Hao Yu,Maegan L Capitano,Zhuangzhuang Geng,Daniel C Link,Sarah C Nabinger,Hal E Broxmeyer,Lindsey D Mayo,Michihiro Kobayashi,Qiang Wang,Gang Huang,Sergio Barajas,Yan Liu

doi:10.1038/s41467-019-13542-2

Abstract

Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated with increased risks of hematological malignancies. While TP53 mutations have been identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic stem and progenitor cell (HSPC) expansion are largely unknown. Here we discover that mutant p53 confers a competitive advantage to HSPCs following transplantation and promotes HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me3 in genes regulating HSPC self-renewal and differentiation. Furthermore, genetic and pharmacological inhibition of EZH2 decreases the repopulating potential of p53 mutant HSPCs. Thus, we uncover an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel therapeutic target for preventing CHIP progression and treating hematological malignancies with TP53 mutations.

Highlights

We have been investigating the role of p53 in normal and malignant hematopoiesis
To determine the impact of TP53 mutations on hematopoietic stem and progenitor cell (HSPC) functions, we introduced eight hot-spot TP53 mutations identified in CHIP4–6,10–12 (Fig. 1c), into WT mouse HSPCs using retrovirusmediated transduction and performed in vitro and in vivo assays (Fig. 1d)
Several pathways important for hematopoietic stem cell (HSC) maintenance, including Regulation of hematopoiesis, Hematopoietic organ development, Immune response, and Positive regulation of cytokine response, were significantly enriched in p53R248W/+ HSPCs compared to p53+/+ HSPCs (Supplementary Fig. 3c)

Summary

Introduction

We have been investigating the role of p53 in normal and malignant hematopoiesis. We discovered that wild-type (WT) p53 maintains hematopoietic stem cell (HSC) quiescence and identified Necdin as a p53 target gene that regulates DNA damage response (DDR) in HSCs20,21. While clinical studies suggest that expansion of HSPCs with TP53 mutations predisposes the elderly to hematological neoplasms[4,5,6,10,11,12], the role of TP53 mutations in CHIP progression remains elusive. Polycomb group (PcG) proteins are epigenetic regulators that have been implicated in stem cell maintenance and cancer development[25,26,27,28]. While EZH2 plays important roles in HSCs and MDS development[16,29,30], its regulation in HSPCs is not fully understood. Mutant p53 interacts with EZH2 and enhances its association with the chromatin, thereby increasing the levels of H3K27me[3] in genes regulating HSPC self-renewal and differentiation. We have uncovered an epigenetic mechanism by which mutant p53 drives clonal hematopoiesis

Methods

Results

Conclusion