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Identification of an E2A-regulated transcriptional network controlling T lineage commitment and transformation.

机译：鉴定E2A调控的转录网络，控制T谱系的定型和转化。

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摘要

The E2A transcription factors are required for proper T lymphopoiesis and to prevent T lymphocyte progenitor transformation. Loss of E2A leads to a decreased number of lymphoid-primed multipotent progenitors (LMPPs) in the bone marrow and T cell progenitors in the thymus. Ectopic expression of E2A proteins in E2A-/- lymphoma results in growth arrest and apoptosis, indicating that these cells remain responsive to the targets of E2A. In this study we showed that E2A-/- progenitor cells from both adult thymus and fetal liver poorly differentiated into committed DN3 cells in vitro but undertook a NK cell program. We found that E2A-/- DN2 cells as well as fetal-derived T cell precursors overproduced Gata3, a transcriptional factor that is also essential for T cell development, however high levels of Gata3 were reported to block T cell lineage commitment and divert progenitors to alternative cell fate. We showed that genetic ablation of one allele of Gata3 restored T cell differentiation in vitro and in vivo in the absence of E2A, suggesting Gata3 expression should be tightly controlled to ensure normal T cell development. Theses findings demonstrated a critical role for E2A in facilitating T cell lineage commitment by restraining the expression of Gata3. We also identified, in this study, the transcriptional repressor growth factor independent 1b (Gfi1b) as a direct target of E2A which promotes growth arrest and apoptosis in E2A-/- lymphomas. Gfi1b represses the expression of Gata3 which is required for the survival of lymphomas and T cell progenitors. We showed that ectopic expression of Gata3 in the T cell lymphomas promotes the expression of Gfi1b, suggesting these proteins may function in an auto regulatory loop to maintain appropriate levels of Gata3. Taken together, our study identified a transcriptional regulatory pathway in which E2A proteins promote T cell lineage commitment as well as prevent lymphoma cell expansion through modulation of Gata3 expression.
机译：E2A转录因子是适当的T淋巴细胞生成和防止T淋巴细胞祖细胞转化所必需的。 E2A的丢失导致骨髓中淋巴启动的多能祖细胞（LMPPs）和胸腺中T细胞祖细胞数量减少。 E2A-/-淋巴瘤中E2A蛋白的异位表达导致生长停滞和细胞凋亡，表明这些细胞仍然对E2A靶标有反应。在这项研究中，我们表明来自成年胸腺和胎儿肝脏的E2A-/-祖细胞在体外难以分化为定型DN3细胞，但进行了NK细胞程序。我们发现E2A-/-DN2细胞以及胎儿来源的T细胞前体过度生产了Gata3，这也是T细胞发育所必需的转录因子，但是据报道，高水平的Gata3阻止T细胞谱系的发生并将祖细胞转移到替代细胞命运。我们表明，在不存在E2A的情况下，Gata3的一个等位基因的遗传消融可在体外和体内恢复T细胞分化，表明应严格控制Gata3的表达以确保正常的T细胞发育。这些发现证明了E2A通过限制Gata3的表达在促进T细胞谱系承诺中起着关键作用。在这项研究中，我们还确定了独立于转录抑制因子生长因子的1b（Gfi1b）是E2A的直接靶标，它可促进E2A-/-淋巴瘤的生长停滞和凋亡。 Gfi1b抑制淋巴瘤和T细胞祖细胞存活所必需的Gata3表达。我们发现，T细胞淋巴瘤中Gata3的异位表达促进了Gfi1b的表达，表明这些蛋白可能在自动调节环路中发挥功能，以维持适当的Gata3水平。综上所述，我们的研究确定了一条转录调节途径，其中E2A蛋白可促进T细胞谱系定型并通过调节Gata3表达来防止淋巴瘤细胞扩增。

著录项

  • 作者

    Xu, Wei.;

  • 作者单位

    The University of Chicago.;

  • 授予单位 The University of Chicago.;
  • 学科 Health Sciences Human Development.;Health Sciences Oncology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 141 p.
  • 总页数 141
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 宗教;
  • 关键词

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