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Cell Stem Cell. 2015 Nov 5;17(5):597-610. doi: 10.1016/j.stem.2015.08.004. Epub 2015 Sep 18.

HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation.

Author information

1
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, CA 91010, USA.
2
Taipei Medical University, Taipei 11031, Taiwan.
3
Institute of Biological Chemistry, Academia Sinica, Taipei 11574, Taiwan.
4
Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, Norbert Gehr and Family Leukemia Center, City of Hope Medical Center, Duarte, CA 91010, USA. Electronic address: ykuo@coh.org.

Abstract

Acute myeloid leukemia (AML) is driven and sustained by leukemia stem cells (LSCs) with unlimited self-renewal capacity and resistance to chemotherapy. Mutation in the TP53 tumor suppressor is relatively rare in de novo AML; however, p53 can be regulated through post-translational mechanisms. Here, we show that p53 activity is inhibited in inv(16)(+) AML LSCs via interactions with the CBFβ-SMMHC (CM) fusion protein and histone deacetylase 8 (HDAC8). HDAC8 aberrantly deacetylates p53 and promotes LSC transformation and maintenance. HDAC8 deficiency or inhibition using HDAC8-selective inhibitors (HDAC8i) effectively restores p53 acetylation and activity. Importantly, HDAC8 inhibition induces apoptosis in inv(16)(+) AML CD34(+) cells, while sparing the normal hematopoietic stem cells. Furthermore, in vivo HDAC8i administration profoundly diminishes AML propagation and abrogates leukemia-initiating capacity of both murine and patient-derived LSCs. This study elucidates an HDAC8-mediated p53-inactivating mechanism promoting LSC activity and highlights HDAC8 inhibition as a promising approach to selectively target inv(16)(+) LSCs.

PMID:
26387755
PMCID:
PMC4636961
DOI:
10.1016/j.stem.2015.08.004
[Indexed for MEDLINE]
Free PMC Article

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