HES1 mediates cell-specific consequences of Notch signaling in ALL

HES1 介导 ALL 中 Notch 信号传导的细胞特异性后果

基本信息

批准号：
8434006
负责人：
Patrick A Zweidler-McKay
金额：
$ 29.14万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8434006
关键词：
Acute Lymphocytic Leukemia Acute leukemia Apoptosis Apoptotic B-Cell Acute Lymphoblastic Leukemia B-Lymphocytes Bone Marrow Cell model Cells ChIP-seq Chronic Lymphocytic Leukemia Coculture Techniques Complex Data Development ES01 Equilibrium Exposure to Gene Expression Gene Family Gene Targeting Genes Goals Growth Human IL2RA gene Inhibition of Apoptosis Lead Ligands Link Lymphoid Measures Mediating Mutation Notch Signaling Pathway Oncogenes Oncogenic Outcome Pathway interactions Patients Phenotype Play Proteins Regulation Repression Role Sampling Signal Transduction System T-Cell Development T-Cell Leukemia T-Cell Proliferation T-Lymphocyte Up-Regulation base cancer therapy caspase-8 cell type clinically relevant genome-wide insight leukemia leukemogenesis mRNA Expression notch protein novel novel strategies prevent public health relevance receptor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Notch signaling is a highly conserved pathway which plays many critical roles throughout development, and is dysregulated during oncogenesis. The consequences of Notch signaling vary by cell type and depend on poorly characterized downstream mechanisms. We and others have observed contrasting roles for Notch in T and B lymphocytes and leukemias which share a common lymphoid precursor. In T cells, Notch promotes commitment and expansion, and constitutive activation leads to T cell proliferation and leukemogenesis. In contrast, Notch signaling inhibits B cell commitment and leads to growth arrest and apoptosis in normal and leukemic B cells. We have found that the Notch downstream gene HES1 is sufficient to induce growth arrest and apoptosis in B cell leukemias, but not T cell leukemias. These findings suggest that HES1 may play a critical role in determining the cell type- specific consequences of Notch signaling. The goal of this project is to elucidate the mechanism(s) by which HES1 alters the consequences of Notch signaling. We propose to use acute leukemia subtypes as a model for these cell-specific differences, and will characterize the role of HES1 in T cell versus B cell leukemias. Our results suggest that PARP1 interaction may be one mechanism, where PARP1 regulates HES1 function and leads to PARP1 cleavage and pro-apoptotic consequences. In addition, HES1 may have an alternate repertoire of transcriptional targets leading to divergent consequences. In Aim 1 we define the cell context-dependent regulation of the HES1 transcriptional complex, with a novel role for PARP1 in altering HES1 function and ties HES1 to the apoptotic cascade. Aim 2 characterizes the transcriptional consequences of HES1 signaling using genome-wide ChIP-SEQ and expression analysis, and characterization of two HES1-regulated genes which may contribute to Notch/HES1-mediated growth inhibition and apoptosis. In Aim 3 we propose to validate our hypothesis in leukemia patient samples through characterization of Notch pathway activation and exploration of the effects of the Notch ligands on these patient samples. Defining the cell context-dependent differences across acute leukemia subtypes will provide important insights into the mechanisms behind the diverse roles of Notch. These insights will inform our understanding of Notch signaling in development and oncogenesis, and may allow us to "tip-the-balance" from Notch-mediated oncogenesis to growth suppression, defining a new paradigm for cancer therapy.

描述（由申请人提供）：Notch 信号传导是一种高度保守的途径，在整个发育过程中发挥许多关键作用，并且在肿瘤发生过程中失调。 Notch 信号传导的后果因细胞类型而异，并且取决于尚未明确表征的下游机制。我们和其他人观察到 Notch 在 T 淋巴细胞和 B 淋巴细胞以及具有共同淋巴前体的白血病中发挥相反的作用。在 T 细胞中，Notch 促进定型和扩张，而组成型激活则导致 T 细胞增殖和白血病发生。相反，Notch 信号传导抑制 B 细胞定向并导致正常和白血病 B 细胞生长停滞和凋亡。我们发现Notch下游基因HES1足以诱导B细胞白血病的生长停滞和细胞凋亡，但不能诱导T细胞白血病。这些发现表明 HES1 可能在确定 Notch 信号传导的细胞类型特异性后果中发挥关键作用。该项目的目标是阐明 HES1 改变 Notch 信号传导结果的机制。我们建议使用急性白血病亚型作为这些细胞特异性差异的模型，并将描述 HES1 在 T 细胞白血病和 B 细胞白血病中的作用。我们的结果表明，PARP1 相互作用可能是一种机制，其中 PARP1 调节 HES1 功能并导致 PARP1 裂解和促凋亡后果。此外，HES1 可能具有导致不同结果的替代转录靶标。在目标 1 中，我们定义了 HES1 转录复合物的细胞环境依赖性调节，其中 PARP1 在改变 HES1 功能并将 HES1 与细胞凋亡级联联系起来方面发挥着新作用。目标 2 使用全基因组 ChIP-SEQ 和表达分析来表征 HES1 信号转导的转录结果，并表征可能有助于 Notch/HES1 介导的生长抑制和细胞凋亡的两个 HES1 调节基因。在目标 3 中，我们建议通过表征 Notch 通路激活并探索 Notch 配体对这些患者样本的影响，在白血病患者样本中验证我们的假设。定义急性白血病亚型之间的细胞环境依赖性差异将为了解 Notch 不同作用背后的机制提供重要见解。这些见解将有助于我们理解Notch信号在发育和肿瘤发生中的作用，并可能使我们能够从Notch介导的肿瘤发生到生长抑制“平衡”，从而定义癌症治疗的新范例。