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: 8762140
• 负责人: YA-HUEI KUO
• 金额: $ 31.72万
• 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/8762140
• 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; public health relevance; self-renewal; small hairpin RNA; stem; stem cell differentiation; 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（由申请人提供）：急性髓性白血病（AML）是成人中最常见的白血病类型，由于耐药性和随后的复发，总体结局较差。可以引发和维持AML的白血病干细胞（LSC）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消除。我们的长期目标是确定调节LSC生成和维持的分子机制，并确定基于新机制的LSC靶向治疗。在AML患者中发现的最常见的染色体畸变之一是16号染色体倒位，其产生编码CBF <$-SMMHC（CM）融合蛋白的融合基因CBFb-MYH 11。本申请的目的是确定组蛋白脱乙酰酶8（HDAC 8）如何促进CM诱导的AML发病机制，确定HDAC 8活性的分子机制，并评价亚型选择性抑制剂（HDAC 8i）靶向人AML LSC的疗效。我们的中心假设是HDAC 8活性通过inv（16）依赖性和非依赖性机制去调节，并且异常的HDAC 8活性通过破坏p53乙酰化而有助于AML LSC转化和维持。因此，通过使用HDAC 8i抑制HDAC 8可以重新激活p53并增强AML LSC的靶向。具体目标是：1）确定HDAC 8如何促进inv（16）诱导的AML发病机制和LSC维持，2）确定HDAC 8活性的潜在机制和HDAC 8亚型选择性药理学抑制剂靶向非inv（16）AML LSC的疗效。在具体目标1中，我们将定义CM如何改变HDAC 8和p53活性;通过使用我们的条件性CM敲入小鼠（也携带新的条件性Hdac 8缺失等位基因）确定HDAC 8在CM诱导的LSC转化和维持中的作用;并验证inv（16）+患者的原发性AML LSC中的发现。在特定目标2中，我们将确定HDAC 8表达与非inv（16）AML LSC中SOX 4和HOXA 9水平或p53状态之间的相关性;确定HDAC 8过表达的功能后果以及HOXA 9/SOX 4轴是否有助于HDAC 8失调;并评估HDAC 8i对p53活性、LSC增殖和治疗抗性的影响。为了评估HDAC 8的功能，我们产生了携带新的条件性Hdac 8缺失等位基因的小鼠。此外，我们将使用shRNA介导的敲低和新型药理学HDAC 8i的组合。这些拟议的研究有望建立HDAC 8失调的分子机制，以及AML发病机制中HDAC 8介导的新型翻译后p53失活机制。此外，这些研究将揭示作用机制以及HDAC 8i是否可以重新激活p53并增强AML LSC的消除。这些结果将为靶向治疗提供新的理论基础和新的HDAC 8亚型选择性药理学抑制剂，并将对AML以及p53未突变的其他癌症类型产生翻译影响。