Molecular Pathways in T Cell Development and Thymic Lymphoma

T 细胞发育和胸腺淋巴瘤的分子途径

• 批准号: 6989689
• 负责人: HARALD VON BOEHMER
• 金额: $ 21.01万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-11 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989689
• 关键词: T cell receptor; T lymphocyte; acute lymphocytic leukemia; athymic mouse; biological signal transduction; carcinogenesis; cell differentiation; cell growth regulation; cytogenetics; flow cytometry; gene expression; gene expression profiling; genetically modified animals; human T cell leukemia; laboratory mouse; leukocyte activation /transformation; lymphoma; microarray technology; molecular oncology; polymerase chain reaction; thymus neoplasms; transcription factor; western blottings

DESCRIPTION (provided by applicant): Intrathymic T cell development proceeds through receptor- controlled checkpoints at which cells with properly assembled T cell receptors (TCR) are rescued from programmed cell death, expand and/or undergo further differentiation. Differentiation is controlled by transcription factors such as Notch1-dependent CSL, Ikaros, b-catenin-dependent TCF1 as well as basic helix loop helix (bHLH) proteins encoded by E2A and HEB genes. Some of the transcription factors control the assembly of the pre-TCR and signaling by the pre-TCR can regulate the function of certain transcription factors. While the binding of E47/HEB heterodimers to E-boxes in the regulatory region of several genes is believed to induce differentiation at the expense of proliferation, interference with that process is believed to result in proliferation at the expense of differentiation. Within this frame we will address the hypotheses that 1) Lymphomagenic abnormalities in gene expression synergize with the pre-TCR in generating T-ALL, 2) that known abnormalities in gene expression resulting in lymphoma affect cell cycle/survival of developing T cells, 3) that in the generation of T-ALL initial abnormalities in gene expression must be followed by further genetic changes, and 4) that similar molecular pathways are involved in murine and human T-ALL over expressing TALl.

描述（由申请人提供）：胸膜T细胞发育通过受体进行 受控的检查点，在该检查点上，将其适当组装的T细胞受体（TCR）的细胞从程序性细胞死亡中救出，扩展和/或经历进一步的分化。分化受转录因子的控制，例如Notch1依赖性CSL，IKAROS，B-Catenin依赖性TCF1以及由E2A和HEB基因编码的基本螺旋环路螺旋（BHLH）蛋白。某些转录因子控制了TRE-TCR的组装和TRE-TCR信号传导可以调节某些转录因子的功能。虽然据信，E47/HEB异二聚体与几个基因调节区域的电子盒的结合被认为以牺牲增殖为代价诱导分化，但认为对该过程的干扰会导致以分化为代价的增殖。在此框架内，我们将解决以下假设：1）基因表达的淋巴瘤异常与生成T-all的pre-TCR协同作用，2）2）已知基因表达中已知异常，导致 淋巴瘤会影响发育中T细胞的细胞周期/存活，3）在T-ALL初始生成中 基因表达的异常必须遵循进一步的遗传变化，而4）相似的分子途径参与了鼠和人类T-All与表达高高相比。