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:
- 金额:$ 19.5万
- 依托单位:
- 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:
- 关键词:AccountingAcute Lymphocytic LeukemiaAcute T Cell LeukemiaAddressAdultAdult Acute Lymphocytic LeukemiaAllelesBHLH ProteinCD8B1 geneCell CycleCell Cycle RegulationCell LineageCell SurvivalCellsChildhoodChildhood Acute Lymphocytic LeukemiaChromosomal translocationCyclin-Dependent Kinase InhibitorDependenceDevelopmentDiseaseDoseE proteinEarly DiagnosisFrequenciesFutureGene MutationGenesGoalsHelix-Loop-Helix MotifsHematopoieticHumanHuman CharacteristicsLeadLymphoblastic LeukemiaLymphomaLymphomagenesisLymphopoiesisMalignant - descriptorMethodsMicroarray AnalysisModelingMolecularMusMutationNatural Killer CellsNotch Signaling PathwayOncogene DeregulationOncogenesPathway interactionsPatientsPhenotypePredispositionProcessProductionProteinsRNARecurrent diseaseRefractory DiseaseRegulationRelapseRepressionResearchSignal TransductionStagingSurvival RateT cell differentiationT-Cell DevelopmentT-Cell LymphomaT-Cell ProliferationT-Cell TransformationT-LymphocyteTCF3 geneTestingThymocyte DevelopmentTimebaseimprovedinhibitor/antagonistinsightleukemialeukemogenesismRNA Expressionnotch proteinolder patientoutcome forecastpreventprogenitorresearch studythymocytetranscription 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(申请人提供):GATA3是T淋巴生成必需的转录因子,但GATA3表达升高可使T细胞分化脱轨,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细胞祖细胞的过度增殖和小鼠T细胞淋巴瘤和人类T淋巴细胞急性淋巴母细胞白血病(T- all)的发展。我们之前已经表明,在E2A- /-小鼠中出现的淋巴瘤与大多数T-ALL共享Notch信号通路的解除管制。然而,E2A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,胸腺细胞发育早期需要E2A来限制Gata3的表达,并且在E2A-/-小鼠中杂合缺失Gata3部分恢复T细胞分化并阻止T细胞祖细胞过度增殖。在这里,我们提出实验来验证GATA3的解除管制导致细胞周期抑制剂的持续抑制,这些抑制剂使T细胞祖细胞容易过度增殖和T细胞转化。我们的假设预测,严格调控GATA3对于T细胞分化而不转化是必要的。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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BARBARA L. KEE其他文献
BARBARA L. KEE的其他文献
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