The role of GATA-3 in T-cell lymphomas

GATA-3 在 T 细胞淋巴瘤中的作用

• 批准号: 8707833
• 负责人: Ryan A Wilcox
• 金额: $ 17.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-26 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707833
• 关键词: B-Cell NonHodgkins Lymphoma; Binding Proteins; Bioinformatics; Biologic Characteristic; Cell Differentiation process; Cell Lineage; Cells; ChIP-seq; Characteristics; Classification; Clinical; Diagnosis; Disease; Exclusion; Foundations; Gene Expression; Gene Expression Profile; Gene Targeting; Genetic Transcription; Genome; Genomics; Goals; Growth; Health; Immunity; Incidence; Knowledge; Link; Lymphoma; Lymphoproliferative Disorders; Malignant - descriptor; Malignant Neoplasms; Molecular; Myelogenous; Non-Hodgkin' s Lymphoma; Normal Cell; Pathogenesis; Peripheral; Phenotype; Population; Production; Regulation; Regulatory T-Lymphocyte; Research; Research Personnel; Role; Specimen; Stromal Cells; T cell differentiation; T memory cell; T-Cell Development; T-Cell Lymphoma; T-Lymphocyte; Testing; Th2 Cells; Therapeutic; Transcriptional Regulation; Tumor Biology; United States; Work; cancer cell; career; cytokine; improved; macrophage; malignant lymphocyte; mouse model; neoplastic cell; novel; outcome forecast; programs; skills; transcription factor; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): The T-cell lymphomas, representing approximately 10% of all non-Hodgkin lymphomas, are heterogeneous, poorly understood, and generally associated with a dismal prognosis. The cell of origin for most T-cell lymphoproliferative disorders has remained elusive and represents a barrier to further advances in this field. Normal T cells, under the influence of specific transcription factors, differentiate into functionally disinct populations following antigenic stimulation. For example, GATA-binding protein 3 (GATA-3) is a transcription factor that controls T-cell differentiation into T helper type 2 (Th2) cells. We have shown that myeloid-derived cells are regulated by cytokines transcriptionally regulated by GATA-3 and that these cells, including lymphoma-associated macrophages, promote the growth and survival of malignant T cells. Therefore, we hypothesized that a subset of T-cell lymphomas may be Th2-cell derived and regulate their microenvironment by producing cytokines that are transcriptionally regulated by GATA-3. In support of this hypothesis, we have found that a subset of T-cell lymphomas with an especially poor prognosis expresses GATA-3 and that its expression is associated with clinical and biologic characteristics resembling Th2 cells. Therefore, we aim to test the hypothesis that GATA-3 expression identifies a previously uncharacterized subset of T-cell lymphomas that exploit a GATA-3 driven transcriptional program to regulate lymphoma-associated macrophages within the tumor microenvironment. This hypothesis may support a novel paradigm in tumor biology with implications that extend beyond the T-cell lymphomas. Namely, transcriptional programs that determine cell lineage and differentiation in malignant cells may regulate stromal cells within the tumor microenvironment that are required for tumor growth.

描述(申请人提供)：T细胞淋巴瘤，约占所有非霍奇金淋巴瘤的10%，是异质性的，了解很少，通常与悲观的预后有关。大多数T细胞淋巴增生性疾病的起源细胞仍然难以捉摸，这是这一领域进一步发展的障碍。正常T细胞在特定转录因子的影响下，在抗原刺激后分化为功能失活的群体。例如，GATA结合蛋白3(GATA-3)是一种转录因子，控制T细胞分化为辅助性T细胞2型(Th2)。我们有 研究表明，髓系细胞受GATA-3转录调控的细胞因子的调节，这些细胞，包括淋巴瘤相关的巨噬细胞，促进了恶性T细胞的生长和存活。因此，我们假设T细胞淋巴瘤的一部分可能是Th2细胞来源的，并通过产生受GATA-3转录调控的细胞因子来调节其微环境。为了支持这一假设，我们发现预后特别差的T细胞淋巴瘤的一部分表达GATA-3，并且其表达与类似Th2细胞的临床和生物学特性有关。因此，我们的目标是检验这样一种假设，即GATA-3的表达识别了以前未表现出特征的T细胞淋巴瘤亚群，该亚群利用GATA-3驱动的转录程序来调节肿瘤微环境中的淋巴瘤相关巨噬细胞。这一假说可能支持肿瘤生物学中的一种新范式，其含义超越了T细胞淋巴瘤。也就是说，决定恶性肿瘤细胞谱系和分化的转录程序可能调节肿瘤微环境中的间质细胞，这是肿瘤生长所必需的。