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

E2A-/- 小鼠中 GATA3 失调和 T 细胞转化

基本信息

批准号：
8189155
负责人：
BARBARA L. KEE
金额：
$ 19.5万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/8189155
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 research study thymocyte transcription factor

项目摘要

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）：GATA3 是 T 淋巴细胞生成的重要转录因子，但 GATA3 表达升高会破坏 T 细胞分化并促进转化。 E2A转录因子也是正常T细胞分化所必需的，E2A的缺失或E2A功能的抑制会导致T细胞祖细胞过度增殖以及小鼠T细胞淋巴瘤和T淋巴细胞急性淋巴细胞白血病（T-ALL）的发展。）在人类中。我们之前已经表明，E2A-/- 小鼠中出现的淋巴瘤与大多数 T-ALL 一样，都存在 Notch 信号通路的失调。然而，E2A 活性降低如何导致 T 细胞转化易感性仍不清楚。我们最近发现，在胸腺细胞发育早期，需要 E2A 来限制 Gata3 的表达，并且 E2A-/- 小鼠中 Gata3 的杂合缺失可以部分恢复 T 细胞分化并防止 T 细胞祖细胞过度增殖。在这里，我们提出实验来检验以下假设：GATA3 的失调会导致细胞周期抑制剂的持续抑制，从而使 T 细胞祖细胞过度增殖和 T 细胞转化。我们的假设预测，GATA3 的严格调控对于允许 T 细胞在不发生转化的情况下分化是必要的。公共健康相关性：我们的实验旨在揭示淋巴瘤发生模型中 T 细胞祖细胞转化的根本基础，该模型与人类 T-ALL 有许多共同点。虽然儿童 ALL 的预后相对较好，但该疾病的某些亚型和复发性 T-ALL 很难治疗。此外，成年T-ALL患者预后较差。了解诱发白血病发生的机制对于提高我们识别有利于疾病出现的条件的能力至关重要，从而改进早期检测方法。此外，我们的实验将深入了解转化过程如何启动以及哪些蛋白质可能成为未来 T-ALL 治疗的靶点。