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: 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
• 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

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多体染色体（额外的chr副本）。21)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体，而21三体（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，我们在Ts1Rhr小鼠的B细胞中发现了异常分化和增强的白血病发生，Ts1Rhr小鼠是人类chr.21上唐氏综合征关键区（DSCR）中存在的31个基因的三体。这些是21三体小鼠模型中首次报道的淋巴细胞特异性表型。我们还定义了一个与DSCR三倍复制相关的B细胞表达特征，该特征富含多梳抑制复合体2 （PRC2）的基因靶点，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，是癌症中常见的突变靶点。最后，对三复制DSCR基因的rna干扰筛选显示，Ts1Rhr B细胞对Hmgn1的敲低有选择性敏感，Hmgn1编码一种核小体结合蛋白，已知可促进染色质松弛和改变组蛋白H3修饰。我们假设21三体通过hmgn1介导的PRC2靶基因表达改变来促进B-ALL。为了进一步确定21号多体、HMGN1和B- all之间的机制联系，并确定21号多体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三倍复制诱导的B细胞转化的贡献。我们将定义具有21染色体多态性的B细胞和B- all细胞的表观遗传景观，并评估组蛋白H3K27标记的遗传和化学调节是否会消除与DSCR三倍相关的转化。(2)确定Hmgn1三倍体对水稻萌发和持续的影响