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

Jing Qi, Sandeep Singh, Wei Kai Hua, Qi Cai, Shi Wei Chao, Ling Li, Hongjun Liu, Yinwei Ho, Tinisha McDonald, Allen Lin, Guido Marcucci, Ravi Bhatia, Wei Jan Huang, Chung I. Chang, Ya Huei Kuo

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)597-610
Number of pages14
JournalCell Stem Cell
Volume17
Issue number5
DOIs
Publication statusPublished - Nov 5 2015

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine
  • Genetics

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    Qi, J., Singh, S., Hua, W. K., Cai, Q., Chao, S. W., Li, L., Liu, H., Ho, Y., McDonald, T., Lin, A., Marcucci, G., Bhatia, R., Huang, W. J., Chang, C. I., & Kuo, Y. H. (2015). HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation. Cell Stem Cell, 17(5), 597-610. https://doi.org/10.1016/j.stem.2015.08.004