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

基本信息

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
项目类别：
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

项目摘要

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，由于治疗耐药和随后的复发，其总体结果较差，可以引发和维持 AML 的白血病干细胞 (LSC) 被认为是潜在的。我们的长期目标是确定调节 LSC 生成和维持的分子机制，并确定基于机制的新型 LSC 靶向治疗。 AML 患者中最常见的染色体畸变是 16 号染色体倒位，它产生了编码 CBF 的融合基因 CBFb-MYH11。 -SMMHC (CM) 融合蛋白。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的功效。 (HDAC8i) 靶向人类 AML LSCs 我们的中心假设是 HDAC8 活性通过 inv(16) 依赖和独立机制解除管制。异常的 HDAC8 活性通过破坏 p53 乙酰化来促进 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) 确定 HDAC8 如何促进 inv(16)-。诱导 AML 发病机制和 LSC 维持，以及 2) 确定 HDAC8 活性的潜在机制和 HDAC8 的功效在特定目标 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 CM 确定 HDAC8 在 CM 诱导的 LSC 转化和维持中的作用。还携带新的条件性 Hdac8 缺失等位基因的敲入小鼠；并验证了 inv(16)+ 患者的原发性 AML LSC 的研究结果。目标 2，我们将确定非 inv(16) AML LSC 中 HDAC8 表达与 SOX4 和 HOXA9 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；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，我们培育了携带新条件的小鼠。此外，我们将结合使用 shRNA 介导的敲低和新型药理学 HDAC8i，预计将建立 HDAC8 失调的分子机制，以及新型 HDAC8 介导的翻译后 p53。此外，这些研究将揭示 HDAC8i 的作用机制以及是否可以重新激活 p53 并增强 AML LSC 的消除。靶向治疗的基本原理和新型 HDAC8 异构体选择性药物抑制剂，并将对 AML 以及 p53 未突变的其他癌症类型产生转化影响。