Mechanisms of Transformation by TAL1/SCL in Thymic Malignancy

T细胞恶性肿瘤的侵袭性和不可预见性继续给儿童和成人带来重大的临床管理问题。这一建议基于以下中心假设：TAL1/SCL介导的转录网络中的下游靶基因有助于大多数人类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控：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分析确定了311个基因，其启动子与TAL1结合，并且也受到TAL1下调的显著上调或下调。这些结果导致了当前的项目提案，该项目试图在三个具体目标上验证上述中心假设：(1)通过鉴定T-ALL/LBL中与TAL1直接结合并受TAL1调控的编码和非编码基因，描述TAL1及其结合伙伴E2A、HeB、GATA3、LMO1和LMO2调控的转录网络；(2)描述TAL1与其转化协作者NOTCHI、MYB和LEF1协同调控的转录网络，以及TAL1在TALL/LBL中直接调控的“第二级”转录因子；以及(3)通过基因敲除或过表达来确定TAL1转化的T-ALL细胞需要哪些调控网络和特异性基因来维持其异常存活和持续生长。与该项目中拥有基因组规模定位分析(Rick Young，项目5)、T细胞发展(Harald von Boehmer，项目2)、细胞周期调节(Piotr Sininski，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互动，将极大地增加从这些目标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.