Direct coregulation of Notch1 by Zmiz1 in T-cell leukemia

T 细胞白血病中 Zmiz1 对 Notch1 的直接共调节

基本信息

批准号：
8982936
负责人：
MARK Y CHIANG
金额：
$ 35.46万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2020-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8982936
关键词：
Acute T Cell Leukemia Adult Adverse effects Alleles Amino Acids Automobile Driving Binding Cancer Etiology Cells Chromatin Clinical Clinical Trials Complex Data Dose Effectiveness Ensure Gene Expression Gene Expression Regulation Gene Targeting Genetic Transcription Goals Health Hematologic Neoplasms Homeostasis Human Intestines Knockout Mice Knowledge Lead Learning Maintenance Malignant Childhood Neoplasm Malignant Neoplasms Maps Mission Modeling Mus Mutation Myeloid Leukemia Myeloproliferative disease NOTCH1 gene Oncogenes Oncogenic Pathway interactions Patients Physiological Public Health Regulation Reporting Research Resistance Role Sampling Signal Transduction Site Solid Specimen T-Cell Leukemia T-Lymphocyte T-Lymphocyte Subsets Technology Tissues Toxic effect Translations Tumor Suppression Tumor Suppressor Proteins Validation Work arm cancer therapy clinically relevant combat efficacy testing inhibitor/antagonist innovation intestinal homeostasis leukemia leukemogenesis mouse model notch protein public health relevance targeted treatment tumor

项目摘要

DESCRIPTION (provided by applicant): The discovery of NOTCH1 as a driver mutation in the majority of human T-ALL cases has raised hopes for targeted therapy in this cancer. NOTCH has also been implicated as an important oncogene in a diverse range of solid and hematologic cancers. However, complete blockade of the Notch pathway is impractical because of intolerable on-target side effects. There is also concern that this would cause cancer. Thus, clinical trials are forced to use lower doses of Notch inhibitors. However, these doses are poorly effective because collaborative networks amplify weak Notch signals and drive resistance. Our long-term goal is to identify and understand the networks that collaborate with Notch. Our preliminary data implicate the PIAS coactivator Zmiz1 as a new direct and selective regulator of Notch1. ZMIZ1 and activated NOTCH1 were co-expressed in a significant subset of primary human T-ALL specimens. Zmiz1 inhibition slowed proliferation and overcame resistance to Notch inhibitors. Here we show co-binding of Zmiz1 and Notch1 at a subset of Notch1 regulatory sites; regulation by Zmiz1 of a subset of Notch1 target genes; and a critical structural domain that attaches Zmiz1 directly to Notch1. Similar to Notch deficiency, Zmiz1 deficiency caused a cell autonomous loss of all T-cell subsets. In contrast to Notch deficiency, Zmiz1 deficiency did not cause myeloproliferative disease or severe GI toxicity. Importantly, deletion of Zmiz1 in established T-ALL led to tumor regression and prolonged survival. Our objective in this application is to elucidate the mechanism by which Zmiz1 enhances Notch1-activated T- ALL. Our central hypothesis is that Zmiz1 regulates an oncogenic subset of Notch1 signals by directly interacting with Notch1 in concert with other factors to drive T-ALL. In our first aim, we will determine the mechanisms by which Zmiz1 and Notch1 selectively co-bind and coregulate an oncogenic subset of Notch target genes. We will map the interactions at the amino acid level. We will identify the factors controlling the selectivity of Zmiz1 in gene regulation. In our second aim, we will use our newly generated Zmiz1 knockout mice to determine the effects of Zmiz1 on leukemia initiating cells. We will learn whether Zmiz1 inhibition could be effectively and safely combined with tolerable doses of Notch inhibitors. Our project is significant because it will elucidate a new direct and selective Notch regulator that is required for T-ALL maintenance and contributes to GSI resistance, but is dispensable for intestinal homeostasis and myeloid tumor suppression. Thus, it may lead to Notch-directed cancer therapy without the unacceptable consequences of pan-Notch inhibition. Our preliminary analysis suggests that Zmiz1 is expressed and functionally active in diverse cancers. Thus, our work may have broad implications. Our project is innovative because it is the first instance, to our knowledge, that a transcriptional regulator directly engages the core Notch complex to heterogeneously regulate Notch target genes. We employ new knockout mice and technologies that raise the standards of human sample validation in the T-ALL field to ensure that our project has the highest potential for clinical translation.

描述（由申请人提供）：NOTCH1 作为大多数人类 T-ALL 病例的驱动突变的发现给这种癌症的治疗带来了希望，NOTCH 也被认为是多种实体和靶向治疗中的重要癌基因。然而，由于无法忍受的靶向副作用，完全阻断Notch通路是不切实际的，因此，临床试验被迫使用较低剂量的Notch。然而，这些剂量的效果很差，因为协作网络会放大微弱的 Notch 信号并驱动耐药性。我们的初步数据表明 PIAS 共激活剂 Zmiz1 是一种新的直接和耐药性。 ZMIZ1 的选择性调节剂和激活的 NOTCH1 在原代人类 T-ALL 样本中共表达，抑制 Zmiz1 可以减缓增殖并克服对 Notch 抑制剂的耐药性。我们展示了 Zmiz1 和 Notch1 在 Notch1 调控位点子集上的共结合；Zmiz1 对 Notch1 靶基因子集和关键结构的调控；与 Notch 缺陷类似，Zmiz1 缺陷会导致所有 T 细胞亚群的细胞自主丧失，而与 Notch 缺陷相反，Zmiz1 缺陷不会导致骨髓增生性疾病或严重的胃肠道毒性。 Zmiz1 在已建立的 T-ALL 中导致肿瘤消退并延长生存期，我们的目的是阐明 Zmiz1 增强 Notch1 激活的 T-ALL 的机制。我们的中心假设是 Zmiz1 通过直接调节 Notch1 信号的致癌子集。与 Notch1 与其他因素相互作用来驱动 T-ALL 在我们的第一个目标中，我们将确定 Zmiz1 和 Notch1 选择性地共同结合和共同调节的机制。我们将在氨基酸水平上绘制出 Notch 靶基因的致癌子集，我们将确定控制 Zmiz1 在基因调控中的选择性的因素。我们的目标是使用新产生的 Zmiz1 敲除小鼠来确定 Zmiz1 对白血病起始细胞的影响，我们将了解 Zmiz1 抑制是否可以有效且安全地与可耐受剂量的 Notch 抑制剂联合使用。新的直接和选择性 Notch 调节剂是 T-ALL 维持所需的，有助于 GSI 抵抗，但对于肠道稳态和骨髓瘤抑制来说是可有可无的。导致Notch导向的癌症治疗，而不会产生泛Notch抑制的不可接受的后果。我们的初步分析表明，Zmiz1在多种癌症中表达并具有功能活性，因此，我们的工作可能具有广泛的意义，因为它是第一个。例如，据我们所知，转录调节因子直接参与核心Notch复合物来异质调节Notch靶基因。我们采用新的基因敲除小鼠和技术来提高T-ALL领域的人类样本验证标准，以确保我们的项目具有最高潜力用于临床翻译。