SATB1-dependent epigenetic regulation of leukemia initiating cells

白血病起始细胞的 SATB1 依赖性表观遗传调控

• 批准号: 8203213
• 负责人: Britta Will
• 金额: $ 5.13万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2011-09-02
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8203213
• 关键词: AT Rich Sequence; Acute Myelocytic Leukemia; Address; Adult; Affinity; Architecture; Binding; Binding Proteins; Binding Sites; Biological Assay; Cell physiology; Cells; Chromatin Remodeling Factor; Chromosome Mapping; Complex; DNA; DNA Methylation; DNA Sequence; Data; Defect; Development; Disease; Embryo; Ensure; Epigenetic Process; Erythroid Progenitor Cells; Gene Activation; Gene Expression; Gene Expression Profiling; Gene Expression Regulation; Gene Mutation; Gene Targeting; Genes; Genetic; Genetic Models; Globin; Goals; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; Individual; Karyotype; Maintenance; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Myelogenous; Nuclear; Outcomes Research; Pathway interactions; Patients; Pattern; Play; Process; Proteins; Regulation; Regulatory Element; Reporting; Research; Role; SPI1 gene; Shapes; Single Nucleotide Polymorphism; Stem cell transplant; Stem cells; Subgroup; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; Tumor Suppressor Genes; Work; base; cell transformation; chromatin immunoprecipitation; chromatin remodeling; epigenomics; gene repression; in vivo; in vivo Model; insight; leukemia; leukemic stem cell; novel; outcome forecast; programs; restoration; self-renewal; stem; stem cell differentiation; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): In the hematopoietic system, the interplay of particular transcription factors instructs normal hematopoietic stem cells (HSC) to function in a precise manner. While it is known that expression deregulation of specific factors in these transcriptional networks disrupts normal HSC function and leads to the formation of leukemia initiating cells (LIC), superordinate gene expression regulation by epigenetic mechanisms, is still poorly understood. We and others have identified a particular chromatin remodeling factor, special AT-rich sequence-binding protein 1 (SATB1) as an important epigenetic factor governing gene expression in normal T-cell and myeloid differentiation, and in leukemia. Our preliminary data show: SATB1 is required for self-renewal function of HSC, sequence alterations within the SATB1-binding site of an upstream regulatory element of the myeloid master regulator PU.1 act as disease modifiers in AML, and while SATB1 is highly expressed in normal hematopoietic stem and progenitor cells, its expression is impaired in AML patient-derived LIC. We hypothesize that this chromatin remodeling protein regulates the function of normal HSC and malignant stem cells. Since epigenetic alterations do not change the DNA sequences and are pharmacologically reversible, they have been regarded as promising targets for therapy. We propose to investigate epigenetic gene regulation by the chromatin-remodeling protein SATB1 in HSC and LIC. The function of SATB1-dependent gene expression regulation in HSC and LIC will be characterized using in vivo models, such as stem cell transplantation assays. Additionally, these functional studies will be accompanied with integrated epigenomic analyses investigating the mechanism of SATB1-dependent HSC and LIC regulation. We will utilize global chromatin immunoprecipitation analysis (ChIP-seq) in combination with gene expression and DNA methylation pattern analysis. Given our observation that SATB1 is down- regulated in LIC of AML patients, binding of SATB1 to low affinity binding sites may be abrogated and cause expression changes of genes involved in the formation or maintenance of LIC. We will restore SATB1 expression in AML patient-derived LIC and evaluate whether this has an anti-leukemic effect. We will characterize SATB1 binding patterns in AML LIC with low and restored SATB1 expression by ChIP-seq combined with gene expression profiling. Genes differentially occupied and expressed will be further functionally analyzed to determine their potential use as therapeutic targets. Our preliminary data make SATB1 a potential paradigm for epigenetic regulation of tumor suppressor genes in leukemia stem cells. Our study will contribute to elucidating novel molecular pathways that can be targeted for the development of LIC-directed epigenetic therapeutic approaches. PUBLIC HEALTH RELEVANCE: Project Narrative Our study will investigate the function of special AT-rich sequence-binding protein 1 (SATB1), a DNA- organizing ('epi-genetic') factor we have found in normal blood stem cells and cells that initiate acute myeloid leukemia (AML). Our preliminary data show that the presence of SATB1 is required to ensure normal blood stem cell function and our observations further suggest that SATB1 critically contributes not only to the function of normal blood stem cells, but also cells that initiate leukemia. The results of our study will add to our current understanding of normal blood cell production and will also identify fundamentally novel pathways and targets for specific, leukemia initiating cell-directed therapies.

描述（由申请人提供）：在造血系统中，特定转录因子的相互作用指示正常的造血干细胞（HSC）以精确的方式起作用。众所周知，这些转录网络中特定因子的表达放松管制会破坏正常的HSC功能，并导致白血病启动细胞的形成（LIC），通过表观遗传机制调节上级基因表达调节，但仍知之甚少。 我们和其他人已经确定了一种特定的染色质重塑因子，特殊的富含富含的序列结合蛋白1（SATB1）是正常T细胞和髓样分化中基因表达的重要表观遗传因子，以及在白血病中。我们的初步数据显示：SATB1是HSC的自我更新功能所必需的，髓样主要调节剂PU.1的上游调节元件的SATB1结合位点的序列改变是AML中的疾病修饰符，而SATB1在正常的血瘤茎和远端细胞中高度表达了SATB1，其表达是在表达的。我们假设该染色质重塑蛋白调节正常HSC和恶性干细胞的功能。由于表观遗传学的改变不会改变DNA序列，并且在药理上是可逆的，因此它们被认为是有希望的治疗靶标。我们建议通过HSC和LIC中的染色质蛋白SATB1进行表观遗传基因调节。 使用体内模型（例如干细胞移植测定法）将表征HSC和LIC中SATB1依赖性基因表达调节的功能。此外，这些功能研究将伴随着研究SATB1依赖性HSC和LIC调节机制的综合表观基因组分析。我们将利用全球染色质免疫沉淀分析（CHIP-SEQ）与基因表达和DNA甲基化模式分析结合使用。鉴于我们认为SATB1在AML患者的LIC中受到调节，因此SATB1与低亲和力结合位点的结合可能会被废除，并导致与LIC形成或维持有关的基因的表达变化。我们将恢复AML患者衍生的LIC中的SATB1表达，并评估这是否具有抗白血病作用。我们将表征AML LIC中的SATB1结合模式，其chip-seq与基因表达分析结合使用，具有低和恢复的SATB1表达。差异化和表达的基因将进一步分析，以确定其潜在用作治疗靶标。 我们的初步数据使SATB1成为白血病干细胞中肿瘤抑制基因表观遗传调节的潜在范例。我们的研究将有助于阐明新的分子途径，这可以针对发展为LIC指导的表观遗传学治疗方法的发展。 公共卫生相关性：项目叙述我们的研究将研究特殊的富富序列结合蛋白1（SATB1）的功能，这是我们在正常血液干细胞和启动急性髓样白血病（AML）的DNA组织（“表E-遗传”）因子的功能。我们的初步数据表明，需要SATB1的存在以确保正常的血干细胞功能，我们的观察结果进一步表明SATB1不仅对正常血干细胞的功能有贡献，而且对启动白血病的细胞贡献。我们的研究结果将增加我们对正常血细胞产生的当前理解，还将确定从根本上新颖的途径和针对特定的白血病启动细胞指导疗法的靶标。