HDAC8: A Promising Therapeutic Target for Acute Myeloid Leukemia

Marco Spreafico, Alicja M. Gruszka, Debora Valli, Mara Mazzola, Gianluca Deflorian, Arianna Quintè, Maria Grazia Totaro, Cristina Battaglia, Myriam Alcalay, Anna Marozzi, Anna Pistocchi

Research output: Contribution to journalArticlepeer-review

Abstract

Histone deacetylase 8 (HDAC8), a class I HDAC that modifies non-histone proteins such as p53, is highly expressed in different hematological neoplasms including a subtype of acute myeloid leukemia (AML) bearing inversion of chromosome 16 [inv(16)]. To investigate HDAC8 contribution to hematopoietic stem cell maintenance and myeloid leukemic transformation, we generated a zebrafish model with Hdac8 overexpression and observed an increase in hematopoietic 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 signaling 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 hematological malignancies. Accordingly, we demonstrated the utility of a highly specific HDAC8 inhibition as a therapeutic strategy in combination with standard chemotherapy.

Original languageEnglish
Article number844
JournalFrontiers in Cell and Developmental Biology
Volume8
DOIs
Publication statusPublished - Sep 4 2020

Keywords

  • AML
  • HDAC8
  • p53
  • PCI-34051
  • WNT
  • zebrafish

ASJC Scopus subject areas

  • Developmental Biology
  • Cell Biology

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