HDAC8 come bersaglio terapeutico per la leucemia mieloide acuta
Figure 1: Analysis of Hdac8 overexpression in zebrafish and apoptosis induced by PCI treatment
(A) Scheme of trunk-tail region of zebrafish embryos: confocal imaging was always performed on the same embryo region, comprising the tip of the yolk sack extension, between the dorsal aorta and the vein; (B) control; (C) hdac8-mRNA injected; (D) PCI-treated hdac8-mRNA injected Tg(CD41:GFP) zebrafish embryos at 3 dpf. Scale bar represents 100 microns. (E) Quantification by FACS of GFPlow-HSCs of (F) control; (G) hdac8-mRNA injected; (H) PCI-treated hdac8-mRNA injected Tg(CD41:GFP) zebrafish embryos at 3 dpf. The results are presented as mean ± SD from three independent experiments. **p<0.01, n.s. = not significant, one-way ANOVA followed by Tukey post-hoc correction. (I) Apoptosis of HSCs in the caudal hematopoietic tissue of the Tg(CD41:GFP) zebrafish line following PCI treatment. GFP+ HSCs in green; activated caspase-3+ cells in red. Arrows indicate double positive cells (yellow). Scale bar represents 100 microns.
Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different haematological neoplasms including a subtype of acute myeloid leukaemia (AML) bearing inv(16). To investigate HDAC8 contribution to haematopoietic stem cell maintenance and myeloid leukaemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in haematopoietic stem/progenitor cells, a phenotype that could be reverted using a specific HDAC8 inhibitor, PCI-34051 (PCI). In addition, we demonstrated that AML cell lines respond differently to PCI treatment: HDAC8 inhibition elicits cytotoxic effect with cell cycle arrest followed by apoptosis in THP-1 cells, and cytostatic effect in HL60 cells that lack p53. A combination of cytarabine, a standard anti-AML chemotherapeutic, with PCI resulted in a synergistic effect in all the cell lines tested. We, then, searched for a mechanism behind cell cycle arrest caused by HDAC8 inhibition in the absence of functional p53 and demonstrated an involvement of the canonical WNT signalling in zebrafish and in cell lines. Together, we provide the evidence for the role of HDAC8 in hematopoietic stem cell differentiation in zebrafish and AML cell lines, suggesting HDAC8 inhibition as a therapeutic target in haematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.
“HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia” Frontiers in Cell and Developmental Biology, 2020 vol.8,pp. 844
Press Release DOI: 10.3389/fcell.2020.00844
Contact: Prof. Anna Pistocchi
This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) (MFAG#18714) and Piano Sostegno alla Ricerca PSR20119_MAROZZI.
Dip. di Biotecnologie Mediche e Medicina Traslazionale
Università degli Studi di Milano
Via F.lli Cervi, 93
20090 Segrate (MI)