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: 7655557
• 负责人: HARALD VON BOEHMER
• 金额: $ 29.84万
• 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/7655557
• 关键词: Address; Affect; Apoptosis; BHLH Protein; Binding; Boxing; Cell Cycle; Cells; Disease model; E-Box Elements; Gene Expression; Generations; Genes; Helix-Turn-Helix Motifs; Human; Lead; Lymphoma; Molecular; Molecular Abnormality; Mus; Mutation; Non-Malignant; Nucleic Acid Regulatory Sequences; Pathway interactions; Process; Protein Overexpression; Receptor Signaling; Risk; Signal Transduction; T-Cell Development; T-Cell Receptor; T-Lymphocyte; TCF3 gene; Testing; Thymic Lymphoma; Transgenic Mice; helix-loop-helix protein differentiation inhibitor; invariant chain; man; receptor; receptor expression; thymocyte; transcription factor

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）：胸腺内T细胞发育通过受体- 控制的检查点，在该检查点处，具有适当组装的T细胞受体（TCR）的细胞被从程序性细胞死亡中拯救出来、扩增和/或经历进一步的分化。分化受转录因子如Notch 1依赖性CSL、Ikaros、b-连环蛋白依赖性TCF 1以及由E2 A和HEB基因编码的碱性螺旋环螺旋（bHLH）蛋白控制。一些转录因子控制前TCR的组装，并且前TCR的信号传导可以调节某些转录因子的功能。虽然认为E47/HEB异二聚体与几个基因的调节区中的E盒的结合以增殖为代价诱导分化，但认为干扰该过程以分化为代价导致增殖。在此框架内，我们将提出以下假设：1）基因表达中的淋巴瘤发生异常与前TCR协同产生T-ALL，2）基因表达中的已知异常导致T-ALL， 淋巴瘤影响发育中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伴随进一步的遗传变化，和4）类似的分子途径参与鼠和人T-ALL过表达TAL 1。