Stage-specific roles for Zmiz1 in Notch-dependent steps of early T-cell development

Zmiz1 在早期 T 细胞发育的 Notch 依赖性步骤中的阶段特异性作用

基本信息

批准号：
9816388
负责人：
MARK Y CHIANG
金额：
$ 49.77万
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：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816388
关键词：
Acute T Cell Leukemia Address Binding Bone Marrow Transplantation Cells Cellular biology Chromatin Clinical Clinical Trials Complex Defect Development Enhancers Genes Genetic Transcription Goals Immune Immune system Immunity Impairment In Vitro Infection Injury Intervention Learning Maintenance Malignant - descriptor Malignant Neoplasms Modeling Mus Mutation NOTCH1 gene Natural regeneration Pathway interactions Patients Pharmaceutical Preparations Play Population Dynamics Proteins Public Health Recovery Research Role Signal Transduction Stem cells T cell differentiation T-Cell Development T-Cell Immunologic Specificity T-Cell Proliferation T-Lymphocyte Testing Therapeutic Thymus Gland Tissues Undifferentiated Withdrawal acute T-cell lymphoblastic leukemia cell acute lymphoblastic leukemia cell cancer therapy cell type chemotherapy chromatin remodeling cofactor combat in vivo inhibitor/antagonist innovation irradiation leukemia leukemogenesis notch protein novel overexpression premature preservation prevent progenitor programs reconstitution recruit thymic regeneration transcription factor

Acute T Cell Leukemia Address Binding Bone Marrow Transplantation Cells Cellular biology Chromatin Clinical Clinical Trials Complex Defect Development Enhancers Genes Genetic Transcription Goals Immune Immune system Immunity Impairment In Vitro Infection Injury Intervention Learning Maintenance Malignant - descriptor Malignant Neoplasms Modeling Mus Mutation NOTCH1 gene Natural regeneration Pathway interactions Patients Pharmaceutical Preparations Play Population Dynamics Proteins Public Health Recovery Research Role Signal Transduction Stem cells T cell differentiation T-Cell Development T-Cell Immunologic Specificity T-Cell Proliferation T-Lymphocyte Testing Therapeutic Thymus Gland Tissues Undifferentiated Withdrawal acute T-cell lymphoblastic leukemia cell acute lymphoblastic leukemia cell cancer therapy cell type chemotherapy chromatin remodeling cofactor combat in vivo inhibitor/antagonist innovation irradiation leukemia leukemogenesis notch protein novel overexpression premature preservation prevent progenitor programs reconstitution recruit thymic regeneration transcription factor

展开

项目摘要

ABSTRACT The discovery of NOTCH1 mutations in T-cell Acute Lymphoblastic Leukemia (T-ALL) patients raised hopes for pan-Notch inhibitors to treat this cancer. Unfortunately, in clinical trials, these drugs were too toxic because Notch has essential normal functions. Thus, the challenge is to selectively target Notch in T-ALL cells. Since Notch activity requires cofactors at its enhancers to create favorable cell type-specific “chromatin contexts”, we envision that targeting these cofactors might avoid the intolerable effects of pan-Notch inhibition. Thus, our long-term goal is to understand the T-cell biology of Notch cofactors. For example, we discovered that the PIAS-like coactivator Zmiz1 is a direct cofactor of Notch1 that selectively promotes Notch activity at the T-cell specific Myc enhancer. Zmiz1 withdrawal or disrupting the Zmiz1-Notch1 interaction impaired Myc-dependent proliferation of pre-T cells and leukemic blasts. Importantly, ubiquitous inactivation of Zmiz1 did not have major effects on non-T cell tissues, suggesting more T-cell specific effects than Notch inhibition. For this proposal, we observed that the expression of Zmiz1 in pre-T cells dramatically increases from steady state levels during thymic regeneration. Accordingly, the Zmiz1-deficient pre-T cell defect is magnified 4-fold after irradiation compared to steady state. Thus, Zmiz1 is recruited to urgently restore T-cell immunity after cytoreduction. The Zmiz1 pathway might also have therapeutic utility as supraphysiological activation of Zmiz1 expanded pre-T cells and primitive early thymic progenitors (ETPs) in vitro. ETPs were expanded as Zmiz1 restrains Notch- induced T-cell differentiation signals, thereby protecting ETPs from excessive differentiation. Here, our objective is to understand these novel stage-specific roles of Zmiz1. Our hypothesis is that activating the Zmiz1 pathway induces stage-specific transcriptional programs that promote pre-T cell proliferation and ETP maintenance. To test this, we will determine how Zmiz1 is induced during thymic regeneration and how Zmiz1 facilitates transcription factor activities by remodeling chromatin. We will also determine how Zmiz1 manipulates cofactors and target genes to promote undifferentiated ETP proliferation. Finally, we will raise Zmiz1 signals to supraphysiological levels to enhance thymic recovery in vivo. Infection due to prolonged T-cell deficiency after various cancer therapies is a major clinical problem. Pan-Notch activation as a strategy to regenerate the T-lineage is problematic. Supraphysiological Notch activation depletes ETPs by promoting excessive T-cell commitment. In contrast, Zmiz1 preserves ETP cells, promotes proliferation, and by itself cannot induce leukemia. Thus, our project is significant because it will elucidate a direct Notch1 cofactor that drives leukemia and plays important stage-specific roles in enhancing early T-cell proliferation while restraining differentiation. We will learn new strategies to combat leukemia and promote thymic regeneration. Our project is innovative because it investigates the first instance that a Notch cofactor regulates thymic population dynamics in a manner that would promote balanced Notch-induced thymic regeneration.

抽象的在T细胞急性淋巴细胞白血病（T-ALL）患者中发现Notch1突变的发现用于治疗该癌症的泛压抑制剂。不幸的是，在临床试验中，这些药物太毒了，因为 Notch具有必不可少的正常功能。那是挑战是选择性地靶向T-All细胞中的Notch。自从 Notch活动需要增强器的辅助因子才能创建有利的细胞类型特异性“染色质环境”，我们设想靶向这些辅助因子可能会避免pan-notch抑制的抗刺激作用。那，我们的长期目标是了解Notch辅助因子的T细胞生物学。例如，我们发现 PIAS样共激活因子Zmiz1是Notch1的直接辅助因子，有选择地促进T细胞的Notch活性特定的MYC增强剂。 ZMIZ1提取或破坏ZMIZ1-NOTCH1相互作用受损的MYC依赖性前T细胞和白血病爆炸的增殖。重要的是，Zmiz1的普遍存在没有主要对非T细胞的影响说明，表明T细胞比Notch抑制更大。对于这个建议，我们观察到Zmiz1在前T细胞中的表达在此期间从稳态水平急剧增加胸腺再生。彼此之间，辐照后4倍ZMIZ1缺陷的前T细胞缺陷被放大与稳态相比。这就是招募Zmiz1以急切地恢复细胞降低后的T细胞免疫力。这随着Zmiz1的超刻型生理激活的扩展，ZMIZ1途径也可能具有热实用性细胞和原始的早期胸腺祖细胞（ETP）体外。 ETP扩展，因为ZMIZ1限制了Notch- 诱导的T细胞分化信号，从而保护ETP免受过度分化。在这里，我们的目的是了解Zmiz1的这些新颖的阶段特异性作用。我们的假设是激活Zmiz1 途径诱导特定阶段的转录程序，以促进-T细胞增殖和ETP 维护。为了测试这一点，我们将确定在胸腺再生过程中如何诱导Zmiz1以及Zmiz1如何诱导通过重塑染色质来促进转录因子活性。我们还将确定Zmiz1如何操纵辅因子和靶基因，以促进未分化的ETP增殖。最后，我们将提高 ZMIZ1信号向超生理水平，以增强体内胸腺恢复。由于长时间的T细胞感染各种癌症治疗后的缺乏是一个主要的临床问题。泛诺激活作为一种策略再生T-Linege是有问题的。超生理缺口激活通过促进ETP耗尽ETP 过度的T细胞承诺。相反，Zmiz1保留ETP细胞，促进增殖，并自身不能诱发白血病。那是我们的项目重要的，因为它将阐明直接的Notch1辅助因子驱动白血病，并在增强早期T细胞增殖时发挥重要的阶段特异性作用分化。我们将学习与白血病和促进胸腺再生作斗争的新策略。我们的项目具有创新性，因为它首先调查了一个缺口辅因子调节胸腺种群动力学的方式可以促进水位诱导的胸腺再生。