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

• Published in: Cell stem cell Vol. 17; no. 5; pp. 597 - 610
• Main Authors: Qi, Jing, Singh, Sandeep, Hua, Wei-Kai, Cai, Qi, Chao, Shi-Wei, Li, Ling, Liu, Hongjun, Ho, Yinwei, McDonald, Tinisha, Lin, Allen, Marcucci, Guido, Bhatia, Ravi, Huang, Wei-Jan, Chang, Chung-I, Kuo, Ya-Huei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.11.2015
• Subjects: Acetylation - drug effects; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Chromosomes, Human, Pair 16 - genetics; Hematopoietic Stem Cells - metabolism; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Histone Deacetylases - metabolism; Humans; K562 Cells; Leukemia, Myeloid, Acute - drug therapy; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Inbred Strains; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - metabolism; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1934-5909; 1875-9777
• DOI: 10.1016/j.stem.2015.08.004

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. [Display omitted] •CBFβ-SMMHC (CM) forms an aberrant protein complex with p53 and HDAC8•HDAC8 promotes CM-mediated LSC transformation by aberrantly deacetylating p53•HDAC8 inhibition selectively targets inv(16)+ AML CD34+ cells by reactivating p53•Inhibition of HDAC8 eliminates AML propagation and LSC leukemia-initiating activity Qi et al. demonstrate that the inv(16) fusion protein interacts with the tumor suppressor p53 and HDAC8, thereby causing aberrant HDAC8-mediated deacetylation and inactivation of p53. HDAC8 deletion or inhibition selectively depletes LSC activity by reactivating p53, highlighting HDAC8 as an effective therapeutic target to specifically eliminate inv(16) AML LSCs.