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: 7483243
• 负责人: HARALD VON BOEHMER
• 金额: $ 29.67万
• 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/7483243
• 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(申请人提供)：胸腺内T细胞发育通过受体- 具有正确装配的T细胞受体(TCR)的受控检查点，在这些检查点上，细胞从程序性细胞死亡中解救出来，扩张和/或经历进一步分化。分化是由转录因子控制的，如依赖Notch1的CSL、Ikaros、依赖b-catenin的TCF1以及由E2a和heb基因编码的碱性螺旋环螺旋(BHLH)蛋白。一些转录因子控制着Pre-TCR的组装，通过Pre-TCR的信号可以调节某些转录因子的功能。虽然E47/Heb异源二聚体与几个基因调控区的E-box的结合被认为是以牺牲增殖为代价而诱导分化，但干扰这一过程被认为是以牺牲分化为代价导致增殖。在这个框架内，我们将讨论以下假设：1)基因表达的淋巴生成异常与前TCR在产生T-ALL中协同作用，2)已知的基因表达异常导致 淋巴瘤影响发育中T细胞的细胞周期/存活，3)在T-ALL初始生成过程中 基因表达的异常必须伴随着进一步的遗传变化，以及4)小鼠和人类T-ALL过度表达ALL所涉及的相似的分子途径。