Mechanisms of Transformation by TAL1/SCL in Thymic Malignancy

t细胞恶性肿瘤通常具有侵袭性和不可预测的行为，在儿童和成人中继续构成主要的临床管理问题。该建议基于以下核心假设：TAL1/ scl介导的转录网络中的下游靶基因参与了大多数人类t细胞白血病和淋巴瘤（T-ALL/T-LBL）中细胞增殖、分化和凋亡的紊乱调节：Tom Look实验室的Takaomi Sanda与5号项目的Rick Young和Lee Lawton合作获得的结果，通过ChlP-Chip分析确定了311个启动子与TAL1结合的基因，这些基因的启动子也受到TAL1敲碎的显著上调或下调。这些结果导致了当前的项目提案，旨在通过三个具体目标来验证上述中心假设：(1)通过识别TAL1直接结合的编码和非编码基因，以及TAL1在T-ALL/LBL中表达水平受TAL1调节的编码和非编码基因，描绘TAL1及其结合伙伴E2A， HEB, GATA3， LMO1和LMO2调控的转录网络；(2)描绘TAL1与其转化合作者NOTCHI、MYB和LEF1调控的转录网络，以及TAL1在TALL/LBL中直接调控的“第二层”转录因子；(3)通过基因敲除或过表达确定维持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。在这个项目中，与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）、细胞周期调节（Piotr Sicinski，项目3）、染色体稳定性调节（Fred Alt，项目4）和基因表达阵列（Donna Neuberg，生物统计核心）等专业知识的研究人员进行频繁的持续互动，将大大提高从这些目标中产生重要发现的可能性。

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.