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Pathogenesis of Malignant Mesothelioma by the Human Polycomb Complex BAP1-ASXL

人多梳复合物 BAP1-ASXL 引起恶性间皮瘤的发病机制

基本信息

批准号：
9191343
负责人：
FRANK JOSEPH RAUSCHER III
金额：
$ 55.6万
依托单位：
RESEARCH INST OF FOX CHASE CAN CTR
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：
2014-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9191343
关键词：
22q 3p21 Address Affect Asbestos Asbestos-Related Malignant Mesothelioma Automobile Driving BAP1 gene BRCA1 gene Binding Biochemical Biochemistry Biology CDKN2A gene Cancer Family Cell Line Cells Chromatin Chromosome Arm Clinical Complex Cutaneous Melanoma Deubiquitinating Enzyme Development Disease Disease Management Environmental Exposure Enzyme Interaction Epigenetic Process Exposure to Family Fiber Gene Expression Regulation Genes Genetic Genetic Transcription Germ-Line Mutation High-Risk Cancer Histones Human Human Genetics In Vitro Incidence Individual Inherited Investigation Knockout Mice Laboratories Link Malignant Neoplasms Malignant mesothelioma Medical Melanocytic Neoplasm Mesothelial Cell Mesothelial Hyperplasia Mesothelium Molecular Genetics Multiprotein Complexes Mus Mutate Mutation Nature Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nuclear Pathogenesis Pathology Pathway interactions Phenotype Polycomb Prevention Proteins Reporting Resistance Risk Role Sampling Seasons Somatic Mutation Specimen Structure Syndrome Transcriptional Regulation Tumor Biology Tumor Suppression Tumor Suppressor Genes Tumor Suppressor Proteins Uveal Melanoma base disease phenotype disorder prevention enzyme activity enzyme substrate epigenetic regulation gene product genetic analysis genetic approach in vivo insight knock-down mouse model multidisciplinary mutant new therapeutic target novel novel strategies novel therapeutics outcome forecast prognostic protein complex public health relevance reconstitution transcriptome treatment response tumor ubiquitin C-terminal hydrolase ubiquitin isopeptidase

项目摘要

DESCRIPTION (provided by applicant): Malignant mesothelioma (MM) is an aggressive, treatment-resistant cancer linked to asbestos exposure. The genetic basis for MM has historically focused on somatic mutations of CDKN2A and NF2 as key alterations influencing initiation and progression. Very recently, the BAP1 ubiquitin carboxy-terminal hydrolase, first isolated as a Ch. 3p21 tumor suppressor in 1998 (Rauscher Lab), has been strongly implicated as a major player in MM based on genetic analyses. Germline BAP1 mutations were found in two families with a high incidence of MM and other cancers, and somatic BAP1 alterations occurred in MMs, consistent with biallelic inactivation of a tumor suppressor (Testa Lab). Moreover, somatic BAP1 mutations are common in sporadic MMs and in both sporadic and familial uveal melanoma (UM). The genetic and biochemical mechanisms by which BAP1 mutations predispose to MM and UM and how BAP1 interacts genetically with CDKN2A and NF2 to influence MM pathology, prognosis, and therapeutic response are largely unknown. However, the fact that BAP1 encodes a nuclear-localized de-ubiquitinase that binds to ASXL1/2, an obligate polycomb family partner protein that targets histones, strongly suggests a role in epigenetic regulation of gene transcription. Moreover, since binding of BAP1 to ASXL1/2 is required for enzyme activity and tumor suppression, an alternative way to inactivate BAP1 tumor suppressor activity may be to mutate or silence ASXL1/2 genes. To define both the biochemical mechanisms and the genetic interactions among BAP1, ASXL1/2, CDKN2A and NF2 in MM, the Rauscher and Testa Labs have joined forces to pursue the following Specific Aims: 1) Use a direct in vivo genetic approach to determine if heterozygous Bap1-mutant (+/mut) mice are predisposed to the development of various spontaneous tumors, including MM, and accelerate asbestos-induced MM. 2) Use conditional knockout mice to determine if somatic loss of Bap1 alone in the mesothelium is capable of driving mesothelial hyperplasia and/or frank MM, and if somatic Bap1 inactivation combined with loss of Nf2 and Cdkn2a results in more rapid development and/or a more aggressive disease phenotype, with potential prognostic and novel therapeutic implications. 3) Define the spectrum of BAP1 and ASXL1/2 mutations in human MM specimens/cell lines and determine how these mutations affect binding and function of BAP1 in complex with ASXL1/2 and other PR-DUB complex proteins, and define the transcriptome and cellular phenotype which are altered as a consequence of changes (via knockdown and reconstitution) in BAP1 and other PR-DUB components in MM cells. 4) Determine the composition of the native PR-DUB macromolecular protein complexes that contain wild- type BAP1 and ASXL1/2 in mesothelial cells and in BAP1- and/or ASXL1/2-deficient MM cells to compare normal- and tumor-specific subunit structure and the role of these complexes in epigenetic dysregulation. The proposed multipronged studies by two PIs with complementary expertise represent a comprehensive approach to yield novel insights into MM pathogenesis while providing new targets for therapy and prevention.

描述（由申请人提供）：恶性间皮瘤（MM）是一种侵袭性、难治性癌症，与石棉暴露有关。 MM 的遗传基础历来集中于 CDKN2A 和 NF2 的体细胞突变，作为影响起始和进展的关键改变。最近，BAP1 泛素羧基末端水解酶首次作为 Ch 被分离出来。 1998 年，Rauscher 实验室发现 3p21 肿瘤抑制因子，根据遗传分析，该基因被认为是 MM 的主要参与者。在 MM 和其他癌症高发的两个家族中发现了种系 BAP1 突变，并且 MM 中发生了体细胞 BAP1 改变，这与肿瘤抑制因子的双等位基因失活一致（Testa Lab）。此外，体细胞 BAP1 突变在散发性 MM 以及散发性和家族性葡萄膜黑色素瘤 (UM) 中很常见。 BAP1 突变导致 MM 和 UM 的遗传和生化机制，以及 BAP1 如何与 CDKN2A 和 NF2 基因相互作用影响 MM 病理、预后和治疗反应，目前尚不清楚。然而，BAP1 编码一种与 ASXL1/2（一种针对组蛋白的专性多梳家族伴侣蛋白）结合的核定位去泛素酶，这一事实强烈表明其在基因转录的表观遗传调控中的作用。此外，由于酶活性和肿瘤抑制需要 BAP1 与 ASXL1/2 的结合，因此灭活 BAP1 肿瘤抑制活性的另一种方法可能是突变或沉默 ASXL1/2 基因。为了明确多发性骨髓瘤中 BAP1、ASXL1/2、CDKN2A 和 NF2 之间的生化机制和遗传相互作用，Rauscher 和 Testa 实验室联手追求以下具体目标：1) 使用直接体内遗传方法确定杂合 Bap1 突变 (+/mut) 小鼠是否容易发生各种自发性肿瘤，包括 MM，并加速石棉诱发MM。 2) 使用条件敲除小鼠来确定间皮中 Bap1 的体细胞缺失是否能够驱动间皮增生和/或明显的 MM，以及体细胞 Bap1 失活与 Nf2 和 Cdkn2a 的缺失相结合是否会导致更快的发展和/或更侵袭性的疾病表型，具有潜在的预后和新的治疗意义。 3) 定义人类 MM 标本/细胞系中 BAP1 和 ASXL1/2 突变的谱，并确定这些突变如何影响 BAP1 与 ASXL1/2 和其他 PR-DUB 复合蛋白复合物的结合和功能，并定义由于 MM 细胞中 BAP1 和其他 PR-DUB 成分的变化（通过敲低和重建）而改变的转录组和细胞表型。 4) 确定间皮细胞和 BAP1 和/或 ASXL1/2 缺陷的 MM 细胞中含有野生型 BAP1 和 ASXL1/2 的天然 PR-DUB 大分子蛋白复合物的组成，以比较正常和肿瘤特异性亚基结构以及这些复合物在表观遗传失调中的作用。两位具有互补专业知识的 PI 提出的多管齐下的研究代表了一种综合方法，可以对 MM 发病机制产生新的见解，同时为治疗和预防提供新的目标。