Mechanisms of Transformation by TAL1/SCL in Thymic Malignancy

TAL1/SCL 在胸腺恶性肿瘤中的转化机制

基本信息

批准号：
7780946
负责人：
A. THOMAS LOOK
金额：
$ 60.44万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-15 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7780946
关键词：
14q11 Acute Lymphocytic Leukemia Adult Adverse effects Affect Agreement Alleles Apoptosis Behavior Binding Biological Assay Biostatistics Core Blast Cell Cell Cycle Cell Cycle Regulation Cell Death Cell Line Cell Proliferation Cell Proliferation Regulation 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 Delivery Systems 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 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

项目摘要

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，继续给儿童和成人带来重大的临床管理问题。该提议基于这样一个中心假设：TAL1/SCL 介导的转录网络中的下游靶基因导致大多数人类 T 细胞白血病和淋巴瘤 (T-ALL/T -LBL)：Tom Look 实验室的 Takaomi Sanda 与项目 5 的 Rick Young 和 Lee Lawton 合作获得的结果，通过 ChlP-Chip 鉴定了 311 个其启动子与 TAL1 结合的基因分析，并且 TAL1 敲低也会显着上调或下调。这些结果导致了当前的项目提案，该提案旨在通过三个具体目标来检验上述中心假设：（1）通过识别 TAL1 及其结合伙伴 E2A、HEB、GATA3、LMO1 和 LMO2 调控的转录网络。 T-ALL/LBL中与TAL1直接结合且表达水平受TAL1调节的编码基因和非编码基因； (2) 描绘TAL1与其转化合作者NOTCHI、MYB和LEF1共同调控的转录网络，以及TALL/LBL中TAL1直接调控的“第二层”转录因子； (3)通过基因敲低或过度表达来确定维持TAL1转化的T-ALL细胞的异常存活和持续生长需要哪些调控网络和特定基因。与该项目中具有基因组规模定位分析（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（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。