ETS1-dependent combinatorial control of oncogenic transcription in Notch-activated T-ALL

Notch激活的T-ALL中致癌转录的ETS1依赖性组合控制

• 批准号: 10733945
• 负责人: MARK Y CHIANG
• 金额: $ 44.14万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733945
• 关键词: Acute T Cell Leukemia; Adult; Affect; Binding; Cell Proliferation; Cells; Child; Childhood; Chromatin; Chromatin Remodeling Factor; Clinical Trials; Collaborations; Complex; DNA Repair; DNA amplification; Data; Development; Dose Limiting; Drosophila genus; ETS1 gene; Elements; Enhancers; Gene Expression; Genetic Enhancer Element; Genetic Transcription; Goals; Health; Impairment; Intestines; Knowledge; Label; Learning; Link; Maintenance; Malignant Neoplasms; Methods; Modeling; NOTCH1 gene; Names; Oncogenes; Oncogenic; Oxidative Phosphorylation; Pathway interactions; Patients; Polymerase; Proliferating; Public Health; Regulatory Element; Repression; Research; Response Elements; Role; Signal Transduction; Site; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Tissues; Toxic effect; Trans-Activators; Transcription Coactivator; Transcriptional Regulation; Withdrawal; Work; acute T-cell lymphoblastic leukemia cell; cell type; chemotherapy; cofactor; combat; combinatorial; deprivation; early phase clinical trial; genome-wide; human model; inhibitor; innovation; intestinal homeostasis; leukemia; leukemogenesis; mouse model; notch protein; programs; promoter; recruit; scaffold; stem; stem cells; targeted agent; targeted treatment; therapeutic target; therapy development; time use; transcription factor

The discovery of NOTCH1 as the most prevalent oncogene in T-cell acute lymphoblastic leukemia (T-ALL) patients raised hopes for targeted therapy in this cancer. Unfortunately, in clinical trials, the pan-Notch inhibitor GSI caused dose-limiting toxicities, particularly intestinal, due to abrogation of Notch functions. Our idea to meet this challenge stems from Drosophila studies showing that Notch requires co-binding transcriptional factor partners at its response elements to generate cell-type specific gene expression programs. If these “Notch- collaborating” transcription factors are hijacked to help drive Notch-induced T-ALL, then inhibiting them might oppose Notch signals and circumvent GSI toxicities. Thus, our long-term goal is to identify Notch-collaborating transcription factors and determine their potential as safe, therapeutic targets. In our preliminary data, we show that ETS1 is the top-ranked Notch-associated transcription factor in the context of T cells, but not intestinal cells. Compared to GSI, the effects of Ets1 inactivation were just as deleterious to T-ALL cells but were much milder on intestinal homeostasis and overall health in mouse models. Mechanistically, we show that CDC73, the scaffold component of the polymerase-associated factor complex (PAF1C), binds ETS1 and is recruited to activate ETS1 response elements. One of these elements is a previously unrecognized but highly conserved superenhancer, which we have tentatively labeled “E-Me” for “ETS1-dependent MYB enhancer”. Our objective is to determine the effects of Ets1-dependent trans-factors and cis-elements on the control of oncogenic transcriptional programs in Notch-activated T-ALL. We hypothesize that disrupting the ETS1-dependent combinatorial control of transcriptional elements by targeting CDC73 or the E-Me will safely repress Notch- induced T-ALL. To test this, we will determine the effects of inhibiting Ets1-dependent factors like Cdc73 on leukemia maintenance in mouse and human models of T-ALL. We will also determine the effects of inhibiting Ets1-dependent factors on oncogenic transcriptional programs and cis-element activation. Finally, we will determine the role of the E-Me element where trans-acting factors are recruited by ETS1 to collectively drive the oncogenic MYB effector pathway. Our work raises the possibility of targeting co-binding Notch-collaborating transcriptional regulators like Ets1 that create the chromatin context that directs Notch functions. Here we will establish Cdc73 as the bridge that connects Ets1 to transcriptional machinery and chromatin modifiers that activate promoters and enhancer elements and highlight E-Me as an important example. Therefore, if successful, our project is significant because we target the #1 ranked Notch-associated cofactor in a cancer to disable Notch- driven oncogenic signals without the toxicities of pan-Notch inhibitors seen in clinical trials. This project is innovative because, to our knowledge, no other Notch cofactor besides ETS1 has been shown to physically recruit Notch to chromatin genome-wide with strong statistical and orthogonal rigor and with a strikingly high convergence of Notch cofactor and Notch binding motifs that was validated by chromatin profiling.

发现 NOTCH1 是 T 细胞急性淋巴细胞白血病 (T-ALL) 中最常见的癌基因 不幸的是，在临床试验中，泛Notch抑制剂给患者带来了针对这种癌症的靶向治疗的希望。 由于 Notch 功能的废除，GSI 引起了剂量限制性毒性，特别是肠道毒性。 这一挑战源于果蝇研究，该研究表明 Notch 需要共结合转录因子 如果这些“Notch-”与它的反应元件合作，生成细胞类型特异性基因表达程序。 “协作”转录因子被劫持以帮助驱动 Notch 诱导的 T-ALL，然后抑制它们可能会 对抗 Notch 信号并规避 GSI 毒性，因此，我们的长期目标是识别 Notch 合作。 在我们的初步数据中，我们展示了转录因子并确定它们作为安全治疗靶点的潜力。 ETS1 是 T 细胞而非肠细胞中排名最高的 Notch 相关转录因子。 与 GSI 相比，Ets1 失活的影响对 T-ALL 细胞同样有害，但要温和得多 从机制上讲，我们展示了 CDC73 对小鼠模型肠道稳态和整体健康的影响。 聚合酶相关因子复合物 (PAF1C) 的支架成分，结合 ETS1 并被募集到 激活 ETS1 反应元件之一是以前未被识别但高度保守的元件。 superenhancer，我们暂时将其标记为“E-Me”，表示“ETS1 依赖的 MYB 增强剂”。 目的是确定Ets1依赖性反式因子和顺式元件对控制致癌物质的影响 我们努力破坏Notch激活的T-ALL中的转录程序。 通过靶向 CDC73 或 E-Me 对转录元件进行组合控制将安全地抑制 Notch- 为了测试这一点，我们将确定抑制 Ets1 依赖性因子（如 Cdc73）对 T-ALL 的影响。 我们还将确定抑制 T-ALL 小鼠和人类模型中的白血病维持的效果。 Ets1 依赖性因素对致癌转录程序和顺式元件激活的影响 确定 E-Me 元件的作用，其中 ETS1 招募反式作用因子共同驱动 我们的工作提出了靶向共结合Notch协作的可能性。 像 Ets1 这样的转录调节因子可以创建指导 Notch 功能的染色质环境。 建立 Cdc73 作为连接 Ets1 与转录机器和染色质修饰剂的桥梁 激活启动子和增强子元件并突出E-Me作为一个重要的例子因此，如果成功的话， 我们的项目意义重大，因为我们的目标是癌症中排名第一的 Notch 相关辅因子，以禁用 Notch- 该项目是在没有临床试验中发现的泛Notch抑制剂毒性的情况下驱动致癌信号的。 创新性是因为，据我们所知，除了 ETS1 之外，没有其他 Notch 辅助因子被证明可以在物理上发挥作用。 以强大的统计和正交严谨性以及惊人的高招募Notch到染色质全基因组 Notch 辅因子和 Notch 结合基序的融合已通过染色质分析进行验证。