Analysis of the role of immune deficiency in E2A-/- T cell lymphomagenesis

免疫缺陷在E2A-/- T细胞淋巴瘤发生中的作用分析

• 批准号: 8959799
• 负责人: BARBARA L. KEE
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8959799
• 关键词: 1 year old; Acute Lymphocytic Leukemia; Acute T Cell Leukemia; Address; Adult; Affect; Age; American; Applications Grants; Biological Assay; Biological Models; Bone Marrow; Bone Marrow Cells; Cell Count; Cells; Cellularity; Characteristics; Child; Childhood; Chimera organism; Chromosomal translocation; DNA Binding; DNA Sequence Alteration; Data; Defect; Development; Disease; Engraftment; Etiology; Gene Expression; Genes; Genetic Transcription; Hematopoietic; Hematopoietic System; High Prevalence; Human; Immune; Immune system; Incidence; Kidney; LYL1 gene; Lead; Lobe; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Modeling; Molecular Profiling; Mus; Mutation; Oncogenes; Population; Predisposition; Proteins; RNA Sequences; Role; T-Cell Development; T-Cell Lymphoma; T-Cell Transformation; T-Lymphocyte; T-Lymphocyte Subsets; TAL1 gene; TCF3 gene; Testing; Transplantation; Treatment outcome; Tumor Suppressor Genes; Tumor Suppressor Proteins; capsule; cell type; combat; cytokine; insight; novel; prevent; progenitor; programs; public health relevance; reconstitution; research study; thymocyte; transcription factor; transcriptome sequencing; treatment response

 DESCRIPTION (provided by applicant): T lymphocyte lineage acute lymphoblastic leukemia is a malignancy that occurs in children and adults and is predicted to increase in incidence as the average age of the American population increases. While multiple oncogenes and tumor suppressors have been implicated in this disease greater than 60% of T-ALL cases have mutations that decreased the function of the E2A transcription factors. Moreover, mice lacking E2A proteins develop a T-ALL-like malignancy, a finding that led to the hypothesis that E2A proteins are tumor suppressors. In this grant application we will test an opposing hypothesis, that the immune deficiency created by loss of E2A proteins results in a loss of early thymocyte progenitor competition and that this loss of competition drives the development of T-ALL like disease. We will test our hypothesis by examining the ability of wild-type thymocyte progenitors to suppress transformation of E2A-deficient thymocytes and by testing whether the degree of immune deficiency in E2A-deficient mice is sufficient to promote transformation of WT cells using a novel model of thymic engraftment. We will also test the impact of increasing thymocyte progenitor competition on the gene expression program of E2A-deficient T cell progenitors to identify gene signatures that are regulated by immune deficiency as opposed to E2A-deficiency. Our experiments will provide significant insight into the mechanism of T cell transformation and may reveal that immune system decline is a precursor to T-ALL susceptibility.

 描述（由申请人提供）：T 淋巴细胞谱系急性淋巴细胞白血病是一种发生在儿童和成人中的恶性肿瘤，预计其发病率会随着美国人口平均年龄的增加而增加。虽然多种癌基因和肿瘤抑制基因与这种疾病有关，但超过 60% 的 T-ALL 病例存在降低 E2A 转录因子功能的突变。此外，缺乏E2A蛋白的小鼠会患上T-ALL样恶性肿瘤，这一发现引发了E2A蛋白是肿瘤抑制因子的假设。在本次拨款申请中，我们将测试一个相反的假设，即 E2A 蛋白缺失造成的免疫缺陷会导致早期胸腺细胞祖细胞竞争的丧失，而这种竞争的丧失会导致 T-ALL 样疾病的发展。我们将通过检查野生型胸腺细胞祖细胞抑制 E2A 缺陷型胸腺细胞转化的能力，并通过使用新型胸腺植入模型测试 E2A 缺陷型小鼠的免疫缺陷程度是否足以促进 WT 细胞的转化来检验我们的假设。我们还将测试增加胸腺细胞祖细胞竞争对 E2A 缺陷 T 细胞祖细胞基因表达程序的影响，以确定受免疫缺陷（而不是 E2A 缺陷）调节的基因特征。我们的实验将提供对 T 细胞转化机制的重要见解，并可能揭示免疫系统衰退是 T-ALL 易感性的先兆。