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Identifying Functional Drivers of MYC Activation via Developmental Enhancers in Diffuse Large B-cell Lymphoma

Identifying Functional Drivers of MYC Activation via Developmental Enhancers in Diffuse Large B-cell Lymphoma
通过发育增强剂识别弥漫性大 B 细胞淋巴瘤中 MYC 激活的功能驱动因素
批准号:
10207556
负责人:
RUSSELL James Hubbard RYAN
金额:
$35.34万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-07-01 至 2025-06-30

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中文摘要
翻译
项目总结/摘要 癌基因MYC的过表达是大多数高危弥漫性大B细胞淋巴瘤的特征, 对于淋巴瘤模型的存活至关重要。然而,只有一半的DLBCL被分配到高风险亚组, 通过基因表达谱分析发现,生发中心样(GCB)-DLBCL的活化基因重排, MYC和MYC重排在另一种常见的高风险亚型ABC-DLBCL中更不常见。 目前对导致MYC基因转录失调的机制了解不多, 在MYC和免疫球蛋白基因之间不存在激活基因组重排的DLBCL 基因座(MYC-IG)。该提案的总体目标是通过远端转录调控来确定MYC调控的新机制。 增强剂。我们的长期目标是利用这种理解来开发改进的治疗策略和/或 DLBCL患者的预测性生物标志物。我们的工作假设是MYC的转录激活 维持DLBCL所需的蛋白质依赖于少量必需的远端蛋白质的顺式调节活性。 增强子模块,位于更大的“超级增强子”区域内。这些模块位于 在8 q24上的MYC基因座的3'区域内(在没有MYC重排的DLBCL中),或在基因组中, 重排伴侣基因座,如3q 27,这是最常见的非IG MYC重排 伙伴我们将利用高通量CRISPR干扰分析来进行强大的功能询问, 在缺乏MYC的DLBCL细胞系中存在于8 q24和3q 27中的复杂的、多模块的“超级增强子” 重排(Aim 1)或携带t(3;8)(q27;q24)重排(Aim 2)。已经识别 离散的远端增强子元件,需要MYC激活,我们将利用一组互补的 实验方法,包括增强子序列的遗传缺失或突变,染色质 免疫沉淀、报告基因测定、体外DNA-蛋白质结合测定和反式因子的扰动, 上游途径来表征这些元素的调节。我们的初步数据表明, 3 ′ MYC增强子区域内的增强子模块对于具有不同畸变的DLBCL是必需的 影响选择性结合必需增强子模块的反式因子。这些异常包括各种 信号和遗传事件,激活NF-κ B因子,或交替,超活化的辅激活OCA- B和一组协同作用的发育转录因子。我们将评估 在t(3;8)重排的背景下,MYC激活依赖于MEF 2B调节的MYC的“劫持”。 增强子模块通常负责致癌基因BCL 6的激活。一旦成功 完成拟议的研究,我们希望严格定义多种不同的机制, 增强子和相关的反式因子可以驱动DLBCL中的MYC转录激活。我们的创新 通过复杂的多模块远端调控识别癌基因激活的关键机制的方法 增强子可以作为在多种癌症类型中进行类似研究的模型。
英文摘要
PROJECT SUMMARY / ABSTRACT Overexpression of the oncogene MYC is characteristic of most high-risk diffuse large B-cell lymphomas, and is essential for the survival of lymphoma models. However, only half of DLBCLs assigned to high-risk subgroups of germinal center-like (GCB)-DLBCL by gene expression profiling bear activating genomic rearrangements of MYC, and MYC rearrangements are even less frequent in another common high-risk subtype, ABC-DLBCL. There is currently a poor understanding of the mechanisms that lead to MYC transcriptional dysregulation in DLBCL in the absence of an activating genomic rearrangement between MYC and an immunoglobulin gene locus (MYC-IG). The overall objective of this proposal is to define novel mechanisms of MYC regulation by distal enhancers. Our long-term goal is to use this understanding to develop improved therapeutic strategies and / or predictive biomarkers for DLBCL patients. Our working hypothesis is that transcriptional activation of MYC required to sustain DLBCL is dependent on the cis-regulatory activity of a small number of essential distal enhancer modules, located within much larger “super-enhancer” regions. These modules are located either within the 3’ region of the MYC locus on 8q24 (in DLBCL without MYC rearrangement), or in a genomic rearrangement partner locus such as 3q27, which is among the most common non-IG MYC rearrangement partners. We will utilize high-throughput CRISPR-interference profiling to perform robust functional interrogation of complex, multi-modular “super-enhancers” present in 8q24 and 3q27 in DLBCL cell lines that lack MYC rearrangements (Aim 1), or bear t(3;8)(q27;q24) rearrangements (Aim 2) respectively. Having identified the discrete distal enhancer elements that are required for MYC activation, we will utilize a complementary set of experimental approaches, including genetic deletion or mutation of enhancer sequences, chromatin immunoprecipitation, reporter assays, in vitro DNA-protein binding assays, and perturbation of trans factors and upstream pathways to characterize the regulation of these elements. Our preliminary data suggests that distinct enhancer modules within the 3’ MYC enhancer region are essential for DLBCLs with different aberrations affecting trans factors that selectively bind the essential enhancer modules. These aberrations include diverse signaling and genetic events that activate NF-kB factors, or alternately, hyperactivation of the coactivator OCA- B and a set of synergistically acting developmental transcription factors. We will evaluate the extent to which MYC activation in the context of a t(3;8) rearrangement is dependent on “hijacking” of MEF2B-regulated enhancer modules that are typically responsible for activation of the oncogene BCL6. Upon successful completion of the proposed research, we expect to rigorously define multiple distinct mechanisms by which enhancers and associated trans-factors can drive MYC transcriptional activation in DLBCL. Our innovative approach for identifying the key mechanisms underlying oncogene activation by complex multi-modular distal enhancers may serve as a model for similar investigations in a wide variety of cancer types.
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Identifying Functional Drivers of MYC Activation via Developmental Enhancers in Diffuse Large B-cell Lymphoma
  • 批准号:
    10412020
  • 项目类别:
  • 资助金额:
    $35.33万
  • 财政年份:
    2020
  • 负责人:
    RUSSELL James Hubbard RYAN
  • 依托单位:
Identifying Functional Drivers of MYC Activation via Developmental Enhancers in Diffuse Large B-cell Lymphoma
  • 批准号:
    10654743
  • 项目类别:
  • 资助金额:
    $34.62万
  • 财政年份:
    2020
  • 负责人:
    RUSSELL James Hubbard RYAN
  • 依托单位:
Oncogenic programs driven by notch signaling in B-cell lymphoma
  • 批准号:
    9751805
  • 项目类别:
  • 资助金额:
    $16.56万
  • 财政年份:
    2017
  • 负责人:
    RUSSELL James Hubbard RYAN
  • 依托单位:
Oncogenic programs driven by Notch signaling in B-cell lymphoma
  • 批准号:
    9164788
  • 项目类别:
  • 资助金额:
    $18.04万
  • 财政年份:
    2016
  • 负责人:
    RUSSELL James Hubbard RYAN
  • 依托单位:
海外基金