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

Abstract

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.

Role of HDACs in normal and malignant hematopoiesis

“…Another class I member HDAC8 is highly expressed in LT-HSCs, MPP and LMPP cells. HDAC8 plays a pivotal role in the maintenance and functional integrity of LT-HSC by deacetylating p53 [25].…”

Protein arginine methyltransferase 1 is required for maintenance of normal adult hematopoiesis

“…5B), indicating that the hematopoietic changes in PRMT1 KO animals were caused by cell autonomous. Consistently, others also used transplant assay to evaluate the cell autonomous effect [33][34][35]. But we can't exclude the possible non-cell autonomous effects.…”

HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

“…Interestingly, high HDAC8 expression was detected not only in inv(16)+ AML CD34+ cells, but also in non-inv(16)+ AML CD34+ cells, suggesting a more general involvement of HDAC8 in AML development (Qi et al, 2015). The role of HDAC8 in AML onset is further supported by a recent finding of it playing a crucial role in maintaining long-term HSC under stress condition by inhibiting p53 (Hua et al, 2017).…”