title: HDAC8 Inhibition Specifically Targets Inv(16) Acute Myeloid Leukemic Stem Cells by Restoring p53 Acetylation.
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.
authors.affiliation: 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.
authors.forename: Jing
authors.initials: J
authors.lastname: Qi
authors.affiliation: 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.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Singh
authors.affiliation: 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.
authors.forename: Wei-Kai
authors.initials: WK
authors.lastname: Hua
authors.affiliation: 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.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cai
authors.affiliation: Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Shi-Wei
authors.initials: SW
authors.lastname: Chao
authors.affiliation: 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.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Yinwei
authors.initials: Y
authors.lastname: Ho
authors.affiliation: 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.
authors.forename: Tinisha
authors.initials: T
authors.lastname: McDonald
authors.affiliation: 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.
authors.forename: Allen
authors.initials: A
authors.lastname: Lin
authors.affiliation: 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.
authors.forename: Guido
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: 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.
authors.forename: Ravi
authors.initials: R
authors.lastname: Bhatia
authors.affiliation: Taipei Medical University, Taipei 11031, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: Institute of Biological Chemistry, Academia Sinica, Taipei 11574, Taiwan.
authors.forename: Chung-I
authors.initials: CI
authors.lastname: Chang
authors.affiliation: 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.
authors.forename: Ya-Huei
authors.initials: YH
authors.lastname: Kuo
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; C409470:HDAC8 protein, human; D006655:Histone Deacetylases