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，总体结果较差。能够引发和维持 AML 的白血病干细胞 (LSC) 被认为是复发的潜在来源，因为标准化疗无法有效消除它们。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。 AML 患者中最常见的染色体畸变之一是 16 号染色体倒位，从而产生编码 CBF-SMMHC (CM) 融合蛋白的融合基因 CBFb-MYH11。本申请的目的是确定组蛋白脱乙酰酶 8 (HDAC8) 如何促进 CM 诱导的 AML 发病机制，确定 HDAC8 活性的分子机制，并评估异构体选择性抑制剂 (HDAC8i) 在靶向人类 AML LSC 方面的功效。我们的中心假设是，HDAC8 活性通过 inv(16) 依赖性和独立机制而失调，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 的靶向性。具体目标是：1) 明确 HDAC8 如何促进 inv(16) 诱导的 AML 发病机制和 LSC 维持，2) 确定 HDAC8 活性的潜在机制以及 HDAC8 亚型选择性药物抑制剂在靶向非 inv(16) AML LSC 方面的功效。在具体目标 1 中，我们将定义 CM 如何改变 HDAC8 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 Hdac8 缺失等位基因）确定 HDAC8 在 CM 诱导的 LSC 转化和维持中的作用；并验证来自 inv(16)+ 患者的原发性 AML LSC 的研究结果。在具体目标 2 中，我们将确定非 inv(16) AML LSC 中 HDAC8 表达与 SOX4 和 HOXA9 水平或 p53 状态之间的相关性；确定 HDAC8 过度表达的功能后果以及 HOXA9/SOX4 轴是否有助于 HDAC8 失调；并评估 HDAC8i 对 p53 活性、LSC 增殖和治疗耐药性的影响。为了评估 HDAC8 的功能，我们培育了携带新的条件性 HDAC8 缺失等位基因的小鼠。此外，我们将结合使用 shRNA 介导的敲低和新型药理学 HDAC8i。拟议的研究预计将建立 HDAC8 失调的分子机制，以及 AML 发病机制中 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。这些结果将为靶向治疗提供新的原理和新的 HDAC8 同工型选择性药物抑制剂，并将对 AML 以及 p53 未突变的其他癌症类型产生转化意义。