Mechanisms of Transformation by TAL1/SCL in Thymic Malignancy

TAL1/SCL 在胸腺恶性肿瘤中的转化机制

• 批准号: 8454432
• 负责人: A. THOMAS LOOK
• 金额: $ 63.97万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8454432
• 关键词: 14q11; Acute; Adult; Adverse effects; Affect; Agreement; Alleles; Apoptosis; Behavior; Binding; Biological Assay; Biostatistics Core; Blast Cell; CD8B1 gene; Cell Cycle; Cell Cycle Regulation; Cell Death; Cell Line; Cell Proliferation; Cell Proliferation Regulation; Cell Survival; Cells; Child; Chromosomal Rearrangement; Chromosomal Stability; Chromosomal translocation; Chromosome Band; Clinical Management; Code; Collaborations; DNA Damage; DNA Sequence; DNA Sequence Rearrangement; Data; Defect; Dependence; Development; Disease; Drug Targeting; Enhancers; Event; Failure; Functional RNA; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Profiling; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genome; Genomics; Goals; Growth; Human; Institutes; LMO2 gene; Laboratories; Lead; Link; Location; Malignant - descriptor; Malignant Neoplasms; Measurement; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Profiling; Mus; NOTCH1 gene; Oncogenic; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Proteins; RNA Interference; Regulation; Regulator Genes; Regulatory Pathway; Relapse; Research; Research Personnel; Role; Staging; T-Cell Development; T-Cell Immunologic Specificity; T-Cell Leukemia; T-Cell Transformation; T-Lymphocyte; TAL1 gene; TCF3 gene; TRA@ gene cluster; Technology; Testing; Therapeutic Intervention; Thymocyte Development; Work; antileukemic agent; base; cell growth; cell transformation; chemotherapy; chromatin immunoprecipitation; gene repression; genome-wide; improved; inhibitor/antagonist; innovation; knock-down; leukemia/lymphoma; new technology; novel; novel therapeutic intervention; overexpression; poly(L-glutamic acid(60)-L-alanine(30)-L-tyrosine(10)); progenitor; programs; promoter; response; small hairpin RNA; small molecule; thymocyte; transcription factor; treatment strategy

The often aggressive and unpredictable behavior of T-cell malignancies continues to pose major clinical management problems in children and adults. This proposal is based on the central hypothesis that downstream target genes within TAL1/SCL-mediated transcriptional networks contribute to the disordered regulation of cell proliferation, differentiation, and apoptosis in the majority of human T-cell leukemias and lymphomas (T-ALL/T-LBL): Results from Takaomi Sanda in Tom Look's laboratory, obtained in collaboration with Rick Young and Lee Lawton of project 5, identified 311 genes whose promoters are bound by TAL1 by ChlP-Chip analysis and that are also significantly up- or down-regulated by TAL1 knock-down. These results led to the current project proposal, which seeks to test the above central hypothesis in three specific aims: (1) delineate the transcriptional networks regulated by TAL1, and its binding-partners E2A, HEB, GATA3, LMO1 and LMO2, by identifying both the coding and non-coding genes directly bound by TAL1 and whose expression levels are regulated by TAL1 in T-ALL/LBL; (2) Delineate the transcriptional networks regulated by TAL1 in concert with its transformation collaborators NOTCHI, MYB and LEF1, and the "second-tier" transcription factors directly regulated by TAL1 in TALL/LBL; and (3) Determine by gene knock-down or over-expression which regulatory networks and specific genes are required to maintain the aberrant survival and the sustained growth of T-ALL cells transformed by TAL1. Frequent ongoing interactions with investigators in this program with expertise in genome-scale location analysis (Rick Young, Project 5), T-cell development (Harald von Boehmer, Project 2), cell cycle regulation (Piotr Sicinski, Project 3), regulation of chromosome stability (Fred Alt, Project 4), and gene expression arrays (Donna Neuberg, Biostatistics Core), will greatly enhance the likelihood of generating important discoveries from these aims.

T细胞恶性肿瘤通常具有侵袭性和不可预测的行为，继续在儿童和成人中造成主要的临床管理问题。这一建议是基于中心假设，即TAL 1/SCL介导的转录网络中的下游靶基因有助于大多数人T细胞白血病和淋巴瘤中细胞增殖、分化和凋亡的无序调节（T-ALL/T-LBL）：来自汤姆·洛克实验室的Takaomi Sanda的结果，与项目5的Rick Young和Lee Lawton合作获得，通过ChIP-Chip分析鉴定了311个基因，其启动子被TAL 1结合，并且也被TAL 1敲低显著上调或下调。这些结果导致了当前的项目提案，其试图在三个具体目标中检验上述中心假设：（1）通过鉴定T-ALL/LBL中TAL 1直接结合的编码和非编码基因以及其表达水平受TAL 1调节的基因，描绘TAL 1及其结合伙伴E2 A、HEB、GATA 3、LMO 1和LMO 2调节的转录网络;（2）阐明TALL/LBL中TAL 1与其转化合作者NOTCHI、MYB和LEF 1共同调控的转录网络，以及TAL 1直接调控的“二级”转录因子;和（3）通过基因敲低或过表达来确定哪些调控网络和特异性基因是维持T细胞异常存活和持续生长所必需的。TAL 1转化的ALL细胞。与该计划中具有基因组规模定位分析专业知识的研究人员进行频繁的持续互动（Rick Young，项目5），T细胞发育（Harald von Boehmer，项目2），细胞周期调控（Piotr Sicinski，项目3），染色体稳定性的调节（Fred Alt，项目4）和基因表达阵列（Donna Neuberg，生物统计学核心），将大大提高从这些目标中产生重要发现的可能性。