Clinical and Genetic Origins of Monomorphic Epitheliotropic Intestinal T Cell Lymphoma

单形性上皮性肠 T 细胞淋巴瘤的临床和遗传起源

基本信息

  • 批准号:
    10566317
  • 负责人:
  • 金额:
    $ 41.66万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

ABSTRACT Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare but lethal disease with a median survival of 1 year. There is no current effective standard-of-care. Previous MEITL sequencing efforts performed by our group and others have revealed SETD2 as one of the most frequently altered genes in this disease. SETD2 directs trimethylation of the lysine 36 residue on histone H3 (H3K36me3), which in turn is associated with active transcription of genes. SETD2 has been implicated in DNA damage repair and mRNA splicing. However, the molecular role of SETD2 and its interaction with activated oncogenes in MEITL pathogenesis is largely unknown. In this proposal, we will utilize a conditional mouse model to determine how SETD2 loss contributes to the creation of a premalignant pool of intestinal intraepithelial cells (IELs), the cell of origin of MEITL. We will also investigate how the combination of SETD2 loss and activation of the oncogenes STAT5B or MYC lead to IEL transformation. Finally, we will determine the extent to which SETD2 deficiency sensitizes T lymphoma cells to a variety of genotoxic chemotherapeutics. We anticipate that the results of this work will have immediate impact on the design of effective treatment regimens that target MEITL and other SETD2-deficient lymphomas.
抽象的 单形性上皮性肠 T 细胞淋巴瘤 (MEITL) 是一种罕见但致命的疾病,中位死亡率 存活1年。目前没有有效的护理标准。之前进行的 MEITL 测序工作 我们的团队和其他人发现 SETD2 是这种疾病中最常改变的基因之一。 SETD2 指导组蛋白 H3 (H3K36me3) 上赖氨酸 36 残基的三甲基化,这反过来又与 具有活跃的基因转录。 SETD2 与 DNA 损伤修复和 mRNA 剪接有关。 然而,SETD2 的分子作用及其与 MEITL 发病机制中激活的癌基因的相互作用尚不清楚。 很大程度上不为人所知。 在本提案中,我们将利用条件小鼠模型来确定 SETD2 损失如何影响 创建肠上皮内细胞 (IEL) 癌前池,即 MEITL 的起源细胞。我们还将 研究 SETD2 缺失和癌基因 STAT5B 或 MYC 激活的组合如何导致 IEL 转变。最后,我们将确定 SETD2 缺陷使 T 淋巴瘤细胞对 多种基因毒性化疗药物。我们预计这项工作的结果将产生立竿见影的影响 设计针对 MEITL 和其他 SETD2 缺陷淋巴瘤的有效治疗方案。

项目成果

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Sandeep Dave其他文献

Sandeep Dave的其他文献

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{{ truncateString('Sandeep Dave', 18)}}的其他基金

Genetic Origins of Adverse Outcomes in African Americans with Lymphoma
非裔美国人淋巴瘤不良后果的遗传起源
  • 批准号:
    10587289
  • 财政年份:
    2023
  • 资助金额:
    $ 41.66万
  • 项目类别:
Targeting histone methylation in PTCL
PTCL 中的靶向组蛋白甲基化
  • 批准号:
    10477033
  • 财政年份:
    2019
  • 资助金额:
    $ 41.66万
  • 项目类别:
Targeting histone methylation in PTCL
PTCL 中的靶向组蛋白甲基化
  • 批准号:
    9791868
  • 财政年份:
    2019
  • 资助金额:
    $ 41.66万
  • 项目类别:
Targeting histone methylation in PTCL
PTCL 中的靶向组蛋白甲基化
  • 批准号:
    10673103
  • 财政年份:
    2019
  • 资助金额:
    $ 41.66万
  • 项目类别:
Targeting histone methylation in PTCL
PTCL 中的靶向组蛋白甲基化
  • 批准号:
    10249204
  • 财政年份:
    2019
  • 资助金额:
    $ 41.66万
  • 项目类别:
Targeting histone methylation in PTCL
PTCL 中的靶向组蛋白甲基化
  • 批准号:
    10005242
  • 财政年份:
    2019
  • 资助金额:
    $ 41.66万
  • 项目类别:
Defining the Functional Role of Mutations in Diffuse Large B cell Lymphoma
定义突变在弥漫性大 B 细胞淋巴瘤中的功能作用
  • 批准号:
    9040901
  • 财政年份:
    2015
  • 资助金额:
    $ 41.66万
  • 项目类别:
The genetics of hepatosplenic T cell lymphoma
肝脾T细胞淋巴瘤的遗传学
  • 批准号:
    8880794
  • 财政年份:
    2015
  • 资助金额:
    $ 41.66万
  • 项目类别:
Exome-wide screening for common mutations in lymphoma
淋巴瘤常见突变的全外显子组筛查
  • 批准号:
    8190377
  • 财政年份:
    2011
  • 资助金额:
    $ 41.66万
  • 项目类别:
Exome-wide screening for common mutations in lymphoma
淋巴瘤常见突变的全外显子组筛查
  • 批准号:
    8279186
  • 财政年份:
    2011
  • 资助金额:
    $ 41.66万
  • 项目类别:

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