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（由适用提供）：急性髓细胞性白血病（AML）是成年人中最常见的白血病类型，由于耐药性和随后的缓解，总体预后较差。可以启动和维持AML的白血病干细胞（LSC）被认为是潜在的救济来源，因为标准化疗没有有效消除它们。我们的长期目标是定义调节LSC生成和维护的分子机制，并确定基于机制的新型LSC靶向疗法。 AML患者发现的最常见的染色体畸变之一是染色体16染色体，该染色体产生了编码CBF.-SMMHC（CM）融合蛋白的融合基因CBFB-MYH11。该应用的目标是定义组蛋白脱乙酰基酶8（HDAC8）如何促进CM诱导的AML发病机理，定义HDAC8活性下的分子机制（S），并评估同工型抑制剂（HDAC8I）在靶向人AML LSC中的有效性。我们的中心假设是，通过INV（16）依赖性和非依赖性机制，HDAC8活性受到解析，并且异常的HDAC8活性通过破坏p53乙酰化而有助于AML LSC转化和维持。因此，使用HDAC8I抑制HDAC8可能会重新激活p53并增强AML LSC的靶向。具体目的是：1）定义HDAC8如何对INV（16）诱导的AML发病机理和LSC维持以及2）确定HDAC8活性的机制以及HDAC8 HDAC8同工型选择性药物抑制剂的效率（S）在靶向非INV（16）AML LSC中的效率。在特定目标1中，我们将定义CM如何改变HDAC8和P53的活动；通过使用条件CM敲入小鼠，还可以确定HDAC8在CM诱导的LSC转化和维护中的作用，该小鼠还带有新的条件HDAC8缺失等位基因；并验证INV（16）+患者的原始AML LSC中的发现。在特定目标2中，我们将确定非INV（16）AML LSC中HDAC8表达与SOX4和HOXA9或p53状态的水平之间的相关性；确定HDAC8过表达的功能后果，以及HOXA9/SOX4轴是否有助于HDAC8放松管制；并评估HDAC8I对p53活性，LSC增殖和对治疗的抗性的影响。为了评估HDAC8的功能，我们生成了带有新条件HDAC8缺失等位基因的小鼠。此外，我们将结合shRNA介导的敲低和新型药物HDAC8I的组合。拟议的研究有望建立HDAC8放松管制的分子机制，以及AML发病机理中新型的HDAC8介导的翻译后p53失活机制。此外，这些研究将揭示作用机制以及HDAC8I是否可以重新激活p53并增强AML LSC的消除。该结果将为靶向治疗提供新颖的理由和新型HDAC8同工型选择性药物抑制剂，并对AML以及其他未突变的p53具有转化含义。