HDAC8 Mediated Regulation of Acute Myeloid Leukemia Pathogenesis and Maintenance

HDAC8 介导的急性髓系白血病发病机制和维持的调节

• 批准号: 8925020
• 负责人: YA-HUEI KUO
• 金额: $ 31.75万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-09 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8925020
• 关键词: Acetylation; Acute Myelocytic Leukemia; Adult; Alleles; Apoptosis; Cause of Death; Cell Maintenance; Cell Proliferation; Cells; Chimeric Proteins; Chromosome abnormality; Chromosomes, Human, Pair 16; Core-Binding Factor; Data; Deacetylation; Epigenetic Process; Gene Targeting; Generations; Genetic; Goals; HOXA9 gene; Health; Hematopoietic stem cells; Histone Deacetylase; Human; Knock-in Mouse; MYH11 gene; Maintenance; Malignant Neoplasms; Mediating; Modeling; Molecular; Mus; Mutate; Mutation; Outcome; Pathogenesis; Patients; Population; Populations at Risk; Protein Isoforms; Recruitment Activity; Regulation; Relapse; Relative (related person); Resistance; Role; Source; Survival Rate; TP53 gene; Treatment outcome; United States; Up-Regulation; Work; aged; base; cancer type; cell transformation; chemotherapy; clinically relevant; fusion gene; human MYH11 protein; improved; inhibitor/antagonist; insight; inv(16)(p13; q22); leukemia; leukemic stem cell; mouse model; novel; novel therapeutic intervention; overexpression; progenitor; protein complex; self-renewal; small hairpin RNA; stem; stem cell differentiation; targeted treatment; therapy resistant

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) is the most common type of leukemia in adults and has poor overall outcome because of therapy resistance and subsequent relapse. Leukemia stem cells (LSCs) that can initiate and maintain AML are considered potential sources of relapse because they are not effectively eliminated by standard chemotherapy. Our long-term goals are to define the molecular mechanism(s) regulating LSC generation and maintenance, and to identify novel mechanism-based LSC targeted therapies. One of the most common chromosome aberrations found in AML patients is inversion of chromosome 16, which creates the fusion gene CBFb-MYH11 that encodes the CBF�-SMMHC (CM) fusion protein. The objectives of this application are to define how histone deacetylase 8 (HDAC8) contributes to CM-induced AML pathogenesis, define the molecular mechanism(s) underlying HDAC8 activity and evaluate the efficacy of isoform-selective inhibitors (HDAC8i) in targeting human AML LSCs. Our central hypothesis is that HDAC8 activity is deregulated through both inv(16)-dependent and -independent mechanisms, and that aberrant HDAC8 activity contributes to AML LSC transformation and maintenance by disrupting p53 acetylation. Therefore, inhibiting HDAC8 by using HDAC8i may reactivate p53 and enhance targeting of AML LSCs. The specific aims are: 1) to define how HDAC8 contributes to inv(16)-induced AML pathogenesis and LSC maintenance, and 2) to determine the mechanism(s) underlying HDAC8 activity and the efficacy of HDAC8 isoform-selective pharmacological inhibitors in targeting non-inv(16) AML LSCs. In Specific Aim 1, we will define how CM alters HDAC8 and p53 activities; determine the role of HDAC8 in CM-induced LSC transformation and maintenance by using our conditional CM knock-in mice that also carry a new conditional Hdac8 deletion allele; and validate the findings in primary AML LSCs from inv(16)+ patients. In Specific Aim 2, we will determine the correlation between HDAC8 expression and levels of SOX4 and HOXA9 or p53 status in non-inv(16) AML LSCs; determine the functional consequences of HDAC8 overexpression and whether the HOXA9/SOX4 axis contributes to HDAC8 deregulation; and evaluate the effects of HDAC8i on p53 activity, LSC proliferation and resistance to therapy. To evaluate the function of HDAC8, we have generated mice carrying a new conditional Hdac8 deletion allele. In addition, we will use a combination of shRNA-mediated knockdown and novel pharmacological HDAC8i. The proposed studies are expected to establish molecular mechanism(s) underlying HDAC8 deregulation, as well as a novel HDAC8-mediated post-translational p53 inactivating mechanism in AML pathogenesis. In addition, these studies will reveal mechanisms of action and whether HDAC8i can reactivate p53 and enhance elimination of AML LSCs. The results will offer novel rationales and novel HDAC8 isoform-selective pharmacological inhibitors for targeted therapy, and will have translational implications for AML, as well as other cancer types in which p53 is not mutated.

描述(申请人提供)：急性髓系白血病(AML)是成人中最常见的白血病类型，由于治疗抵抗和随后的复发，总体预后较差。能够启动和维持AML的白血病干细胞(LSCs)被认为是复发的潜在来源，因为它们不能通过标准化疗有效地消除。我们的长期目标是明确调控LSC产生和维持的分子机制(S)，并确定新的基于机制的LSC靶向治疗。在急性髓细胞白血病患者中发现的最常见的染色体异常之一是16号染色体倒位，这产生了融合基因Cbfb-MYH11，编码CBF�-SMMHC(CM)融合蛋白。本应用的目的是明确组蛋白脱乙酰酶8(HDAC8)在CM诱导的AML发病机制中的作用，明确HDAC8活性的分子机制(S)，并评价异构体选择性抑制剂(HDAC8i)靶向人类AML LSCs的有效性。我们的中心假设是，HDAC8的活性通过inv(16)依赖和非独立的机制被解除调控，并且HDAC8的异常活性通过破坏p53的乙酰化而促进AML LSC的转化和维持。因此，用HDAC8i抑制HDAC8可能重新激活P53，增强对AML LSCs的靶向性。其具体目的是：1)明确HDAC8如何在inv(16)诱导的AML发病和LSC维持中起作用；2)确定HDAC8活性的潜在机制(S)以及HDAC8异构体选择性药物抑制剂靶向非inv(16)AML LSC的有效性。在具体目标1中，我们将定义CM如何改变HDAC8和P53的活性；通过使用我们的条件性CM敲入鼠(也携带新的条件性Hdac8缺失等位基因)来确定HDAC8在CM诱导的LSC转化和维持中的作用；并在inv(16)+患者的原代AML LSC中验证发现。在特定的目标2中，我们将确定HDAC8的表达与非inv(16)AML LSCs中Sox4和HOXA9水平或P53状态的相关性；确定HDAC8过表达的功能后果以及HOXA9/Sox4轴是否参与HDAC8的解除调控；以及评估HDAC8i对P53活性、LSC增殖和耐药的影响。为了评估HDAC8的功能，我们产生了携带新的条件性Hdac8缺失等位基因的小鼠。此外，我们将使用shRNA介导的基因敲除和新的药理HDAC8i的组合。这些研究有望建立HDAC8基因失活的分子机制(S)，以及在AML发病机制中新的HDAC8介导的翻译后p53失活机制。此外，这些研究还将揭示HDAC8i的作用机制以及HDAC8i是否能重新激活P53并增强AML LSCs的消除。这一结果将为靶向治疗提供新的理论基础和新的HDAC8异构体选择性药理抑制剂，并将对AML以及其他P53未突变的癌症类型具有翻译意义。