Targeting Chromatin Modifications in Leukemia with Trisomy 21

利用 21 三体靶向白血病中的染色质修饰

基本信息

批准号：
8813538
负责人：
Andrew A Lane
金额：
$ 15.6万
依托单位：
DANA-FARBER CANCER INST
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：
2014-02-27 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8813538
关键词：
Address Advisory Committees Affect Aneuploidy Area B cell differentiation B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes BCR/ABL1 Binding Proteins Biology Blast Cell Cancer Biology Cells Child Chromatin Chromosomes, Human, Pair 21 Communities Complex Constitutional DNA Dana-Farber Cancer Institute Data Databases Development Plans Down Syndrome Environment Enzymes Epigenetic Process Fetal Liver Gene Expression Gene Expression Profile Gene Targeting Genes Genetic Goals Growth HMGN1 gene Health Hematopoiesis Histone H3 Histones Human Human Chromosomes In Vitro Individual Link Lymphoid Lysine Malignant Neoplasms Mediating Mentorship Methyltransferase Modification Molecular Molecular Profiling Mus Mutation Nucleosomes Oncogenic Orthologous Gene Patients Penetrance Phenotype Physicians Polycomb Polysomy RNA Interference Relapse Relaxation Reporting Research Research Personnel Risk Scientist System Therapeutic Training Transcriptional Activation Trisomy base career career development cell transformation chemical genetics chromatin modification defined contribution functional genomics histone modification in vitro Assay in vivo innovation interstitial leukemia leukemogenesis meetings mouse Ts1Rhr mouse model new therapeutic target novel novel strategies outcome forecast overexpression progenitor targeted treatment therapeutic target

项目摘要

DESCRIPTION (provided by applicant): Polysomy 21 (extra copies of chr.21) is the most common acquired aneuploidy in B cell acute lymphoblastic leukemia (B-ALL), and constitutional trisomy 21 (Down syndrome, DS) confers a 20-fold increased risk of B- ALL. The causative molecular mechanisms of this association remain poorly understood. In preliminary studies, we identified abnormal differentiation and enhanced leukemogenesis in B cells from Ts1Rhr mice, which are trisomic for 31 genes present in the Down Syndrome Critical Region (DSCR) on human chr.21. These represent the first lymphoid-specific phenotypes reported in mouse models of trisomy 21. We also defined a B cell expression signature associated with DSCR triplication that is enriched in gene targets of the polycomb repressor complex 2 (PRC2) and highly associated with human DS-ALL. PRC2 is a histone H3 lysine 27 methyltransferase and a frequent target of mutation in cancer. Finally, an RNA-interference screen of the triplicated DSCR genes showed that Ts1Rhr B cells are selectively sensitive to knockdown of Hmgn1, which encodes a nucleosome binding protein known to promote chromatin relaxation and alter histone H3 modifications. We hypothesize that trisomy 21 promotes B-ALL through HMGN1-mediated alterations in PRC2 target gene expression. To further define the mechanistic links between polysomy 21, HMGN1, and B-ALL, and to define novel therapeutic targets in leukemias with polysomy 21, we propose the following Specific Aims: (1) Define the contribution of histone H3 modifications to B cell transformation induced by DSCR triplication. We will define the epigenetic landscape of B cells and B-ALL blasts with polysomy 21, and assess whether genetic and chemical modulation of histone H3K27 marks abrogates transformation associated with DSCR triplication. (2) Determine the effects of Hmgn1 triplication on initiation and persistence of polysomy 21 B-ALL. We will genetically modulate HMGN1 expression and assess effects on gene expression, histone modifications, and leukemogenesis in murine and human B cells with polysomy 21. There are no targeted therapies currently available for patients with polysomy 21 B-ALL. Thus, these studies address an unmet therapeutic need. In addition, this project will develop focused approaches for studying and therapeutically targeting the biologic consequences of cancer-associated copy number alterations. The applicant Dr. Andrew Lane has outlined a five-year career development plan to meet his goal of becoming an independent investigator in translational cancer biology. Dr. Lane has assembled an Advisory Committee of internationally recognized experts to provide scientific and career mentorship. He enlisted collaborators who are experts in cancer epigenetics to provide experimental advice and specific training in the field. Dana-Farber Cancer Institute is the ideal environment for completion of his scientific and career goals, given its outstanding research community and substantial record for training independent physician-scientists.

描述（由申请人提供）：21 polymome（Chr.21的额外副本）是B细胞急性淋巴细胞性白血病（B-ALL）中最常见的非整倍性（B-ALL）和宪法三体术（唐氏综合症，DS）肯定了B-全部增加了20倍B-全部。该关联的致病分子机制仍然很少理解。在初步研究中，我们鉴定了来自TS1RHR小鼠的B细胞中的异常分化和增强的白血病，这对于人类Chr.21的唐氏综合征关键区域（DSCR）中存在的31个基因是三异构体。这些代表了第21次三体菌小鼠模型中报道的第一个淋巴样特异性表型。我们还定义了与DSCR一式固定相关的B细胞表达签名，该签名富含Polycomb Repressor络合物2（PRC2）的基因靶标（PRC2）（PRC2）（PRC2），并与人类DS-ALL高度相关。 PRC2是一种组蛋白H3赖氨酸27甲基转移酶，也是癌症中突变的常见靶标。最后，三式DSCR基因的RNA干扰屏幕表明，TS1RHR B细胞对HMGN1的敲低有选择性地敏感，它编码了已知可促进染色质弛豫和改变组蛋白H3修饰的核小体结合蛋白。我们假设三体第21次通过HMGN1介导的PRC2靶基因表达促进了B-All。为了进一步定义21，HMGN1和B-all polymomy polymome的机械联系，并通过21 polymane polymane定义了白血病中的新型治疗靶标，我们提出了以下具体目的：（1）定义组蛋白H3修饰对通过DSCR诱导的B细胞转化的贡献。我们将通过21多膜定义B细胞的表观遗传景观和B-ALL BLAST，并评估组蛋白H3K27的遗传和化学调节是否标志着消除与DSCR三次固定相关的转化。（2）确定HMGN1三次固定对启动和持久性的影响 21 B-all。我们将在遗传上调节HMGN1表达，并评估对基因表达，组蛋白修饰和用21多膜的人体B细胞的影响。目前尚无针对21 B-all多骨疗法的患者的靶向疗法。因此，这些研究满足了未满足的治疗需求。此外，该项目将开发针对研究和治疗靶向癌症相关拷贝数改变的生物学后果的方法。申请人安德鲁·莱恩（Andrew Lane）博士概述了一项为期五年的职业发展计划，以实现他成为转化癌症生物学独立研究者的目标。莱恩博士已组建了一个国际认可的专家咨询委员会，以提供科学和职业指导。他招募了癌症表观遗传学专家的合作者，以在该领域提供实验建议和特定的培训。鉴于其出色的研究社区以及培训独立医师科学家的杰出记录，达纳 - 法伯癌研究所是完成其科学和职业目标的理想环境。