Mutant p53 Drives Clonal Hematopoiesis through Modulating Epigenetic Pathway

Abstract

24Clonal hematopoiesis of indeterminate potential (CHIP) increases with age and is associated 25 with increased risks of hematological malignancies. While TP53 mutations have been 26 identified in CHIP, the molecular mechanisms by which mutant p53 promotes hematopoietic 27 stem and progenitor cell (HSPC) expansion are largely unknown. We discovered that mutant 28 p53 confers a competitive advantage to HSPCs following transplantation and promotes 29 HSPC expansion after radiation-induced stress. Mechanistically, mutant p53 interacts with 30 EZH2 and enhances its association with the chromatin, thereby increasing the levels of 31 H3K27me3 in genes regulating HSPC self-renewal and differentiation. Further, genetic and 32 pharmacological inhibition of EZH2 decrease the repopulating potential of p53 mutant 33HSPCs. Thus, we have uncovered an epigenetic mechanism by which mutant p53 drives 34 clonal hematopoiesis. Our work will likely establish epigenetic regulator EZH2 as a novel 35 therapeutic target for preventing CHIP progression and treating hematological malignancies 36 with TP53 mutations. 37 38 39 40 4 Clonal hematopoiesis of indeterminate potential (CHIP), also known as age-related clonal 41 hematopoiesis (ARCH), occurs when a single mutant hematopoietic stem and progenitor cell 42 (HSPC) contributes to a significant clonal proportion of mature blood lineages during aging 1-43 3 . CHIP is common in aged healthy individuals and associated with increased risks of de 44 novo and therapy-related hematological neoplasms, including myelodysplastic syndromes 45 (MDS) and acute myeloid leukemia (AML) 4-8 . CHIP is also associated with increased all-46 cause mortality and risk of cardio-metabolic disease [4][5][6] 9 . While these findings suggest that 47 mutations identified in CHIP likely drive disease development, mechanisms by which these 48 mutations promote HSPC expansion are largely unknown [4][5][6][7][8][9] . 49Most individuals with CHIP carry hematological malignancy-associated mutations, 50including DNMT3A, TET2, ASXL1, JAK2, and TP53 4-6 . The TP53 gene, which encodes the 51 tumor suppressor protein p53, ranks in the top five among genes that were mutated in CHIP 52 4-6, 10-12 . p53 bears the usual hallmarks of a transcription factor, with an amino-terminal 53 transactivation domain (TAD), a core DNA-binding domain (DBD) and carboxy-terminal 54 tetramerization (TET) and regulatory domains (REG) [13][14] . It regulates a large number of 55 genes in response to a variety of cellular insults, including oncogene activation, DNA 56 damage, and inflammation, to suppress tumorigenesis [13][14] . TP53 mutations and deletions 57 were found in approximately half of all human cancers, including hematological malignancies 58 [13][14] . Recently, somatic TP53 mutations were identified in CHIP 4-6 . TP53 mutations were 59 also commonly found in therapy-related CHIP 10, 12 . Interestingly, some individuals with Li-60Fraumeni syndrome (LFS), who carry germline TP53 mutations, develop MDS and AML as 61 they age [14][15] . I...

Clonal hematopoietic mutations linked to platelet traits and the risk of thrombosis or bleeding

“…Herein, TP53 maintains the quiescent state of hematopoietic stem cells, and controls DNA damage responses upon cellular stress. 70 In megakaryocytic cells derived from Tp53 knockout mice, cell size and polyploidization were increased due to higher DNA synthesis and decreased apoptosis. In human cell cultures, TP53 knockdown affected the expression of platelet integrins, granule components and cytoskeletal proteins, which was accompanied by functional platelet defects.…”

“…This can down-regulated several genes associated with self-renewal and differentiation of hematopoietic stem cells. 70 A common consequence is expansion of the affected hematopoietic cell clones. Markedly, the TP53 gene is top ranking in mutated genes found in CHIP.…”

Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia

“…In leukemic Lck-Cre tg/+ Pten fl/fl mice, Cluster 1 methylation was only moderately increased compared to CD2-Lmo2 tg samples at the same stage of disease manifestation. Notably, Cluster 1 CpGs were mostly situated in promoter regions (Figure 4B) of lowly expressed genes (Figure 4C)and displayed enrichment for PRC2 target genes and H3K27me3(27,28) at these sites (Supplementary Figure 12, Figure 4D), thus showing similarity with the hypermethylation phenotype of T-ALLs in the human Cluster A. In contrast, we did not find any evidence in these mouse models for potential overlap between murine Cluster 2 or Cluster 3 and the human COSMe Cluster B.To further confirm similarities between murine Cluster 1 and human Cluster A, we subsequently looked at cross-species overlap at the gene level.…”

Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?

“…Recently, three different stressors, including hematopoietic transplantation, cytotoxic therapy and inflammation, have been shown to expand hematopoietic clones. TP53 mutations identified in CHIP confer a competitive advantage to HSCs and HPCs following transplantation through modulating epigenetic pathways [ 52 ]. Considering that common mutations identified in CHIP affect epigenetic modulators, including DNMT3A, ASXL1, and TET2, these findings underscore the importance of dysregulated epigenetic control in CHIP development.…”