GATA3 deregulation and T cell transformation in E2A-/- mice

E2A-/- 小鼠中 GATA3 失调和 T 细胞转化

• 批准号: 8265238
• 负责人: BARBARA L. KEE
• 金额: $ 23.4万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8265238
• 关键词: Accounting; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Address; Adult; Adult Acute Lymphocytic Leukemia; Alleles; BHLH Protein; CD8B1 gene; Cell Cycle; Cell Cycle Regulation; Cell Lineage; Cell Survival; Cells; Childhood; Childhood Acute Lymphocytic Leukemia; Chromosomal translocation; Cyclin-Dependent Kinase Inhibitor; Dependence; Development; Disease; Dose; E protein; Early Diagnosis; Frequencies; Future; Gene Mutation; Genes; Goals; Helix-Loop-Helix Motifs; Hematopoietic; Human; Human Characteristics; Lead; Lymphoblastic Leukemia; Lymphoma; Lymphomagenesis; Lymphopoiesis; Malignant - descriptor; Methods; Microarray Analysis; Modeling; Molecular; Mus; Mutation; Natural Killer Cells; Notch Signaling Pathway; Oncogene Deregulation; Oncogenes; Pathway interactions; Patients; Phenotype; Predisposition; Process; Production; Proteins; RNA; Recurrent disease; Refractory Disease; Regulation; Relapse; Repression; Research; Signal Transduction; Staging; Survival Rate; T cell differentiation; T-Cell Development; T-Cell Lymphoma; T-Cell Proliferation; T-Cell Transformation; T-Lymphocyte; TCF3 gene; Testing; Thymocyte Development; Time; base; improved; inhibitor/antagonist; insight; leukemia; leukemogenesis; mRNA Expression; notch protein; older patient; outcome forecast; prevent; progenitor; public health relevance; research study; thymocyte; transcription factor

DESCRIPTION (provided by applicant): GATA3 is an essential transcription factor for T lymphopoiesis but elevated expression of GATA3 can derail T cell differentiation and promote transformation. The E2A transcription factors are also required for normal T cell differentiation and deletion of E2A, or inhibition of E2A function, results in hyper-proliferation of T cell progenitors and development of T cell lymphoma in mice and T lymphocyte acute lymphoblastic leukemia (T-ALL) in humans. We have previously shown that lymphomas arising in E2A- /- mice share with the majority of T-ALL a deregulation of the Notch signaling pathway. However, how reduced E2A activity results in susceptibility to T cell transformation remains unknown. We recently found that early in thymocyte development E2A is required to limit expression of Gata3 and that heterozygous deletion of Gata3 in E2A-/- mice partially restores T cell differentiation and prevents T cell progenitor hyper- proliferation. Here we propose experiments to test the hypothesis that deregulation of GATA3 leads to sustained repression of cell cycle inhibitors that predispose T cell progenitors to hyper-proliferation and T cell transformation. Our hypothesis predicts that tight regulation of GATA3 is necessary to allow T cell differentiation without transformation. PUBLIC HEALTH RELEVANCE: Our experiments are intended to reveal the underlying basis for transformation of T cell progenitors in a model of lymphomagenesis that has many commonalities with human T- ALL. While childhood ALL has a relatively good prognosis, some subsets of this disease, and relapse T-ALL are hard to treat. In addition, adult patients with T-ALL have a poor prognosis. Understanding the mechanisms that predispose to leukemogenesis is necessary to improve our ability to identify conditions favorable to emergence of disease and thereby improve methods for early detection. In addition, our experiments will provide insight into how the transformation process is initiated and which proteins might be future targets for therapy in T-ALL.

描述（由申请人提供）：GATA 3是T淋巴细胞生成的必需转录因子，但GATA 3的表达升高可破坏T细胞分化并促进转化。E2 A转录因子也是正常T细胞分化所需的，并且E2 A的缺失或E2 A功能的抑制导致T祖细胞的过度增殖和小鼠中T细胞淋巴瘤和人类中T淋巴细胞急性淋巴细胞白血病（T-ALL）的发展。我们先前已经表明，E2 A- /-小鼠中出现的淋巴瘤与大多数T-ALL共享Notch信号通路的失调。然而，E2 A活性降低如何导致对T细胞转化的易感性仍然未知。我们最近发现，在胸腺细胞发育的早期，需要E2 A来限制Gata 3的表达，并且E2 A-/-小鼠中Gata 3的杂合缺失部分地恢复T细胞分化并防止T细胞祖细胞过度增殖。在这里，我们提出的实验来测试的假设，GATA 3的失调导致持续的细胞周期抑制剂，使T细胞祖细胞过度增殖和T细胞转化的抑制。我们的假设预测，GATA 3的严格调控是必要的，允许T细胞分化而不转化。 公共卫生相关性：我们的实验旨在揭示与人类T-ALL具有许多共性的淋巴瘤发生模型中T细胞祖细胞转化的潜在基础。儿童ALL预后相对较好，但部分亚群和复发性T-ALL较难治疗，成人T-ALL预后较差。了解白血病发生的易感机制对于提高我们识别有利于疾病出现的条件的能力，从而改进早期检测方法是必要的。此外，我们的实验将提供深入了解转化过程是如何启动的，以及哪些蛋白质可能成为T-ALL治疗的未来靶点。