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

• 批准号: 9198490
• 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
• 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/9198490
• 关键词: Acute Lymphocytic Leukemia; Address; Advisory Committees; Affect; Aneuploidy; Area; B cell differentiation; B-Cell Acute Lymphoblastic Leukemia; B-Lymphocyte Subsets; B-Lymphocytes; BCR/ABL1; Binding Proteins; Biology; Blast Cell; Cancer Biology; Cells; Chemicals; 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; Hematopoiesis; Histone H3; Histones; Human; Human Chromosomes; In Vitro; Individual; International; 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 screen; Relapse; Relaxation; Reporting; Research; Research Personnel; Risk; Scientist; Stem cells; System; Therapeutic; Training; Transcriptional Activation; Trisomy; career; career development; cell transformation; chromatin modification; defined contribution; differentiated B cell; functional genomics; histone modification; in vitro Assay; in vivo; innovation; interstitial; knock-down; leukemia; leukemogenesis; mouse Ts1Rhr; mouse model; new therapeutic target; novel strategies; novel therapeutics; outcome forecast; overexpression; public health relevance; targeted treatment; therapeutic target

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 多体性（21 号染色体的额外拷贝）是 B 细胞急性淋巴细胞白血病 (B-ALL) 中最常见的获得性非整倍性，而 21 体性三体性（唐氏综合症，DS）使 B-ALL 的风险增加 20 倍。这种关联的致病分子机制仍然知之甚少。在初步研究中，我们发现 Ts1Rhr 小鼠的 B 细胞存在异常分化和增强的白血病发生，这些小鼠的 B 细胞是人类唐氏综合症关键区 (DSCR) 第 21 号染色体上存在的 31 个基因的三体性。这些代表了在 21 三体性小鼠模型中报道的第一个淋巴特异性表型。我们还定义了与 DSCR 三倍体相关的 B 细胞表达特征，该特征富含多梳阻遏复合物 2 (PRC2) 的基因靶标，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，也是癌症中常见的突变靶点。最后，三重 DSCR 基因的 RNA 干扰筛选表明，Ts1Rhr B 细胞对 Hmgn1 的敲低选择性敏感，Hmgn1 编码一种核小体结合蛋白，已知可促进染色质松弛并改变组蛋白 H3 修饰。我们假设 21 三体通过 HMGN1 介导的 PRC2 靶基因表达改变促进 B-ALL。为了进一步明确多体性 21、HMGN1 和 B-ALL 之间的机制联系，并确定多体性 21 白血病的新治疗靶点，我们提出以下具体目标：(1) 确定组蛋白 H3 修饰对 DSCR 三倍体诱导的 B 细胞转化的贡献。我们将定义具有多体性 21 的 B 细胞和 B-ALL 母细胞的表观遗传景观，并评估组蛋白 H3K27 的遗传和化学调节是否标志着废除与 DSCR 三倍体相关的转化。 (2)确定Hmgn1三倍体对启动和持续的影响 多体性 21 B-ALL。我们将对 HMGN1 表达进行基因调节，并评估对 21 型多体性小鼠和人类 B 细胞的基因表达、组蛋白修饰和白血病发生的影响。目前尚无针对 21 型多体性 B-ALL 患者的靶向治疗方法。因此，这些研究解决了未满足的治疗需求。此外，该项目将开发有针对性的方法来研究和治疗癌症相关拷贝数改变的生物学后果。申请人 Andrew Lane 博士概述了一个五年职业发展计划，以实现他成为转化癌症生物学独立研究者的目标。莱恩博士组建了一个由国际知名专家组成的咨询委员会，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来提供该领域的实验建议和具体培训。丹纳法伯癌症研究所因其出色的研究社区和培训独立医师科学家的丰富记录而成为他完成科学和职业目标的理想环境。