HDAC8 promotes hematopoietic stem and progenitor cells proliferation with implications in acute myeloid leukemia

Acute myeloid leukemia (AML) is a group of heterogeneous malignant hematological disorders characterized by genetic and epigenetic changes in hematopoietic stem cells (HSCs) and myeloid progenitors that cause an imbalance between survival, proliferation and differentiation. Histone deacetylase 8 (HDAC8) is a class I HDAC that has been implicated with haematological malignancies, including AML. In blasts from AML patients carrying the inversion of chromosome 16 (inv(16)), HDAC8 aberrantly inactivates p53 through its deacetylation, reducing apoptosis in the HSC compartment and leading to the onset of leukemia. To note, HDAC8 expression was shown to be altered not only in inv(16) AML patients, but also in HSC cells from several types of AML. Additionally, HDAC8 was demonstrated to play a crucial role in promoting long-term hematopoietic stem cell (LT-HSC) maintenance under stress through p53 inhibition. By generating a zebrafish model for hdac8 overexpression we demonstrated that HDAC8 promotes the expansion of hematopoietic stem and progenitor cells (HSPCs) by increasing their proliferation capability. In AML cell lines with high (HL60 and THP-1) or low (OCI-AML5) HDAC8 activity we assessed the efficiency of HDAC8 blocking as a pharmacological approach for AML by taking advantage of the highly specific HDAC8 inhibitor PCI-34051. Upon PCI-34051 treatment, high HDAC8 activity cells proliferation was arrested (HL60, THP-1) or cells underwent apoptosis (THP-1). Similarly, PCI treatment also rescued HSPC expansion in hdac8-overexpressing embryos by specifically increasing apoptosis in this population. HDAC8 dysregulation both in vitro and in vivo, elicited a modulation of the canonical WNT pathway which is frequently dysregulated in acute myeloid leukemia insurgence. Our results suggest that selective inhibition of HDAC8 by PCI-34051 may represent a valuable therapeutic approach in the treatment of AML patients.