HDAC8 regulates long-term hematopoietic stem-cell maintenance under stress by modulating p53 activity.

The maintenance and functional integrity of long-term hematopoietic stem cells (LT-HSCs) is critical for lifelong hematopoietic regeneration. Histone deacetylases (HDACs) modulate acetylation of lysine residues, a protein modification important for regulation of numerous biological processes. Here, we show that is most highly expressed in the phenotypic LT-HSC population within the adult hematopoietic hierarchy. Using an -floxed allele and a dual-fluorescence Cre reporter allele, largely normal hematopoietic differentiation capacity of deficient cells was observed. However, the frequency of phenotypic LT-HSC population was significantly higher shortly after deletion, and the expansion had shifted to the phenotypic multipotent progenitor population by 1 year. We show that -deficient hematopoietic progenitors are compromised in colony-forming cell serial replating in vitro and long-term serial repopulating activity in vivo. Mechanistically, we demonstrate that the HDAC8 protein interacts with the p53 protein and modulates p53 activity via deacetylation. -deficient LT-HSCs displayed hyperactivation of p53 and increased apoptosis under genotoxic and hematopoietic stress. Genetic inactivation of p53 reversed the increased apoptosis and elevated expression of proapoptotic targets and seen in -deleted LT-HSCs. Dramatically compromised hematopoietic recovery and increased lethality were seen in -deficient mice challenged with serial 5-fluorouracil treatment. This hypersensitivity to hematopoietic ablation was completely rescued by inactivation of p53. Altogether, these results indicate that HDAC8 functions to modulate p53 activity to ensure LT-HSC maintenance and cell survival under stress.