Cancer epigenetics: Understanding histone methylation in leukemia stem cells

癌症表观遗传学：了解白血病干细胞中的组蛋白甲基化

基本信息

批准号：
7960980
负责人：
G Greg Wang
金额：
$ 13.61万
依托单位：
ROCKEFELLER UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7960980
关键词：
Accounting Adopted Advisory Committees Affect Alleles Cancer Patient Cancerous Cells Chemicals Chimeric Proteins Chromatin Chromatin Structure Chromosomal translocation Clinical Trials Collection Complex DNA DNA Fingerprinting DNA Methylation DNA Sequence Data Development Dominant-Negative Mutation Down-Regulation Ensure Environment Enzymatic Biochemistry Enzymes Epigenetic Process Euchromatin Family Future Gene Activation Gene Expression Gene Mutation Gene Rearrangement Genetic Transcription Genomics Goals Grant Growth Hematopoietic Hematopoietic Neoplasms Hematopoietic stem cells Histone Deacetylase Inhibitor Histone H3 Histones Human Human Pathology In Vitro Investigation KDM5B gene Knockout Mice Laboratories Lead Light Literature Lysine Malignant Neoplasms Mediating Mentors Methylation Methyltransferase Modeling Molecular Molecular Target Mus Mutation Myeloid Leukemia Myeloproliferative disease Normal tissue morphology Oncogene Proteins Oncogenes Oncogenic Pathway interactions Phase Play Prevention Proteins Recurrence Regulation Research Research Personnel Role Screening procedure Stem cells Structure Techniques Technology Testing Therapeutic Therapeutic Intervention Training Programs Transactivation Transcriptional Regulation Tumor Suppression Tumor Suppressor Proteins base cancer cell cancer diagnosis cancer stem cell cancer type chromatin modification clinically significant demethylation design embryonic stem cell gain of function gain of function mutation genome-wide histone methyltransferase histone modification in vivo inhibitor/antagonist interest leukemia leukemia/lymphoma leukemic stem cell loss of function metaplastic cell transformation mouse model new therapeutic target novel novel therapeutic intervention programs protein complex public health relevance stem cell population tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): My long-term research interest is to investigate epigenetic mechanisms in oncogenesis. Epigenetics is a phenomenon for phenotypic changes caused by DNA sequence-independent alterations such as chromatin modification. The literature has documented a collection of cancerous deregulations that appear specifically to interfere with proper histone modification. Our focus is recurrent chromosomal translocation found in human leukemia, which targets molecular players that regulate a specific chromatin modification- histone H3 tri-methylated at lysine 4 (abbreviated as H3K4Me3). H3K4Me3 is a prominent histone mark associated with euchromatin structure and active transcription. MLL, an H3K4me3-specific methyltransferase enzyme, is a famed leukemia oncogene, and gain-of-function mutation of MLL represents one of the most common aberrations in human leukemia. In keep with these observations, our recent studies demonstrate that a leukemic translocation NUP98-JARID1A disrupts and/or imparts dominant negative effect on H3K4Me3-specific histone demethylases JARID1. As a result, aberrant accumulation of H3K4Me3 marks on a number of oncogenes leads to their transactivation. Our preliminary data also suggests that such a novel epigenetic mechanism transforms normal hematopoietic stem cells (HSCs) to leukemia-initiating stem cells (LSCs). JARID1A was initially isolated as factor to interact with tumor suppressor RB. We hypothesize that JARID1 family histone demethylases, which were found down regulated among human leukemia, belong to a novel class of tumor suppressors in leukemias. During the mentored phase, I will utilize genomic approaches to identify the histone methylation "signatures" that are associated with LSCs and HSCs. A parallel objective in this phase is to establish targeted mouse ES cells that harbor JARID1A/1B inactivation alleles, as well as to develop techniques for in vitro histone enzymology. In the independent phase, I will examine in vivo functions of JARID1 histone demethylases in tumor suppression and/or normal development using knockout mouse models. Active JARID1 enzymes (in form of protein complexes) and their mediated histone demethylation in vitro will also be characterized. An excellent environment and complementary training program provided by laboratories of Dr. David Allis (mentor), Dr. Shahin Rafii (co-mentor), collaborators, and an Advisory Committee will facilitate my research in the mentored phase and ensure a smooth transition to an independent investigator. The proposed research at the independent phase (Year 3-5) will pave the road to launch my future investigation to reveal novel epigenetic mechanisms in oncogenesis and identify 'druggable' targets for novel therapeutics. PUBLIC HEALTH RELEVANCE: Epigenetics is a phenomenon of phenotypic changes caused by alterations that occur on a specific type of DNA-associated protein termed as histone. Epigenetic mechanisms play critical roles in regulating gene expression and defining cellular states, as well as contributing to the onset and development of human pathologies such as cancers. In this project, we focus on some types of leukemia that accounts for a large percentage of human blood cancer patients. However these cases are currently incurable. Investigating the role of affected histone modifier enzymes in tumor prevention will shed light on novel oncogenic mechanisms. It also has clinical significance for cancer diagnosis and therapies. In vitro enzymology established in the study can be adopted in the future for studies of other cancerous alternations and also for screening small molecular inhibitors. For example, one therapeutic idea is to target an unwanted 'hyperactive' histone methyltransferase activity in cancer cells. Importantly, many chromatin modifier enzymes are considered as feasible targets for screening inhibitor chemicals. In summary, studying the molecular basis of epigenetic regulation will promote greater understanding of the development of normal tissue and/or tumors, which in turn, helps to design some novel effective therapeutic intervention for human cancers.

描述（由申请人提供）：我的长期研究兴趣是研究肿瘤发生中的表观遗传机制。表观遗传学是由DNA序列与非依赖性改变（例如染色质修饰）引起的表型变化的现象。文献记录了一系列癌性消失，这些消失是专门干扰适当的组蛋白修饰的。我们的重点是人类白血病中发现的复发性染色体易位，该染色体靶向调节特定染色质修饰 - 组蛋白H3三甲基化在赖氨酸4（缩写为H3K4ME3）。 H3K4ME3是与构象素结构和活性转录相关的突出组蛋白标记。 MLL是H3K4ME3特异性甲基转移酶，是一种著名的白血病癌基因，MLL的功能性突变是人类白血病中最常见的畸变之一。在与这些观察结果保持一致的过程中，我们最近的研究表明，白血病易位NUP98-JARID1A破坏和/或赋予H3K4me3特异性组蛋白脱甲基酶JARID1的主要负面影响。结果，H3K4me3在许多癌基因上的异常积累导致其反式激活。我们的初步数据还表明，这种新型的表观遗传机制将正常的造血干细胞（HSC）转化为白血病发射干细胞（LSC）。 JARID1A最初被分离为与肿瘤抑制RB相互作用的因素。我们假设JARID1家族组蛋白脱甲基酶被发现在人类白血病中被调节，属于白血病中新型的肿瘤抑制剂。在指导阶段，我将利用基因组方法来识别与LSC和HSC相关的组蛋白甲基化“特征”。在此阶段的一个平行目的是建立靶向的小鼠ES细胞，该细胞含有JARID1A/1B灭活等位基因，并开发用于体外组蛋白酶学的技术。在独立阶段，我将使用基因敲除小鼠模型检查肿瘤抑制和/或正常发育中JARID1组蛋白去甲基酶的体内功能。活性JARID1酶（以蛋白质复合物的形式）及其在体外介导的组蛋白脱甲基化也将被表征。戴维·艾利斯（David Allis）博士（导师），Shahin Rafii博士（Co-Intor），合作者和咨询委员会提供的实验室提供了一项出色的环境和补充培训计划独立研究者。在独立阶段（第3-5年）提出的研究将铺平道路，以发起我未来的研究，以揭示肿瘤发生中的新型表观遗传机制，并确定新型治疗剂的“可吸毒”靶标。公共卫生相关性：表观遗传学是表型变化的一种现象，该现象是由特定类型的DNA相关蛋白称为组蛋白的特定类型的变化引起的。表观遗传机制在调节基因表达和定义细胞状态以及有助于人类病理（例如癌症）的发作和发展中起着关键作用。在这个项目中，我们专注于某些类型的白血病，这些白血病占人类血液癌患者的很大一部分。但是，这些案件目前无法治愈。研究受影响的组蛋白修饰酶在预防肿瘤中的作用将揭示新的致癌机制。它在癌症诊断和疗法方面也具有临床意义。将来可以在研究中建立的体外酶学研究其他癌变替代方案，并用于筛选小分子抑制剂。例如，一种治疗想法是靶向癌细胞中不需要的“多活跃”组蛋白甲基转移酶活性。重要的是，许多染色质修饰酶被认为是筛查抑制剂化学物质的可行靶标。总而言之，研究表观遗传调节的分子基础将促进对正常组织和/或肿瘤的发展的更多了解，这反过来又有助于为人类癌症设计一些新颖的有效治疗干预措施。