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淋巴细胞的必不可少的转录因子，但GATA3的表达升高会使T细胞分化和促进转化。 E2A转录因子也需要正常的T细胞分化和E2A的缺失，或者对E2A功能的抑制，导致T细胞祖细胞的过度增殖以及小鼠和T淋巴细胞急性淋巴细胞淋巴细胞淋巴细胞淋巴瘤的发育以及人类中人类的T细胞淋巴瘤的发展。我们先前已经表明，在E2A- / - 小鼠中产生的淋巴瘤与大多数T-All a对Notch信号通路的失调。但是，降低的E2A活性如何导致对T细胞转化的敏感性仍然未知。我们最近发现，在胸腺细胞发育的早期，需要E2A限制GATA3的表达，并且在E2A - / - 小鼠中GATA3的杂合缺失部分恢复了T细胞分化并防止T细胞祖细胞过度增殖。在这里，我们提出了实验，以测试以下假设：GATA3的放松管制导致对细胞周期抑制剂的持续抑制，使细胞周期抑制剂使T细胞祖细胞偏向于超增殖和T细胞转化。我们的假设预测，GATA3的严格调节对于允许T细胞分化而无需转换是必要的。公共卫生相关性：我们的实验旨在揭示T细胞祖细胞转化的基本基础，该模型与人类T-全部具有许多共同点。虽然童年的预后都相对较好，但这种疾病的某些子集和t-all的复发很难治疗。此外，T-All的成年患者预后较差。了解易受性白血病发生的机制对于提高我们识别有利于疾病的疾病的能力是必要的，从而改善了早期检测的方法。此外，我们的实验将提供有关如何启动转化过程以及哪种蛋白质可能是T-ALL治疗的未来靶标。