Role of heat shock factors (Hsfs) in tumorigenesis

热休克因子（Hsfs）在肿瘤发生中的作用

• 批准号: 8632076
• 负责人: NAHID F MIVECHI
• 金额: $ 27万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632076
• 关键词: Acute Lymphocytic Leukemia; Adult Acute Lymphocytic Leukemia; Apoptosis; Apoptotic; Bone Marrow; Cell Aging; Cell Death; Cell Line; Cell Lineage; Cells; Cre-LoxP; DNA Damage; Data; Development; Disease; Disease remission; Dose; Elderly; Excision; Exhibits; Family member; Frequencies; Genes; Genetic Transcription; Grant; Heat shock factor; Heat-Shock Response; Human; In Vitro; Incidence; Intrinsic factor; Ionizing radiation; Lead; Malignant Neoplasms; Mature T-Lymphocyte; Modeling; Molecular; Molecular Biology; Mus; Mutation; Names; Patients; Pediatrics; Pharmaceutical Preparations; Population; Primary Neoplasm; Process; Proliferating; RNA Sequences; Radiation; Recurrent disease; Relapse; Research Design; Resistance development; Role; Signal Transduction; Specificity; Stem cells; System; T-Cell Development; T-Lymphocyte; TP53 gene; Testing; Therapeutic; Toxic effect; Transplantation; Treatment outcome; Tumor Burden; Tumor Suppressor Genes; Xeno; base; chemotherapy; cohort; design; efficacy testing; exome sequencing; genome-wide; heat shock transcription factor; improved; in vivo; inhibitor/antagonist; leukemia; mouse model; mutant; neoplastic cell; new therapeutic target; outcome forecast; progenitor; protective effect; public health relevance; repaired; research study; response; small hairpin RNA; tumorigenesis

Acute lymphoblastic leukemia (T-ALL) originates from the T cell lineage. The disease represents 15% of pediatrics and 25% of adult ALL cases annually, making it the most common cancer in the very young and elderly populations. Disease relapse occurs frequently, and more than 80% of the relapse T-ALL cases harbor the TP53 mutation. These patients develop resistance to chemotherapy that is associated with very poor prognosis. Furthermore, those patients who do go into remission are faced with severe complications due to their prior aggressive chemotherapy. It is therefore critical to understand the molecular mechanisms that cause and drive T-ALL in order to discover novel therapeutic targets with better specificity and reduced toxicity. Patients with primary and relapse T-ALLs as well as mice with radiation- induced T-ALL have a very high incidence of activated Notch1 and the TP53 mutation. Indeed, TP53-deficient mice exhibit a 70% incidence of ALLs, suggesting that this is a good model for investigating the biology and molecular mechanisms of T-ALL. We have found that deletion of heat shock factors (Hsfs) Hsf4, Hsf2, or Hsf1 in TP53-deficient mice leads to significant protection against development of T-ALL. These data suggest that therapeutic inhibition of Hsfs could be a key to eliminating T-ALL. In this grant, we have designed studies to test the efficacy of hsf deletion in mouse models of T-ALL and track the genome-wide shift in transcription from bone marrow (BM) hemopoietic stem cells (HSCs) to thymic progenitors to mature T cells. Finally, we will examine whether reducing Hsf expression levels in human T-ALL cell lines and primary tumor cells in vitro or inducible deletion of Hsfs in T-ALL-bearing mice will be a good therapeutic option for T-ALLs. We hypothesize that Hsfs are not essential for T cell development; however, they cooperate with oncogenes and tumor suppressor genes to control T-ALL development, and depletion of Hsfs result in the inability of T-ALL cells to survive. Aim 1 will determine the efficacy of Hsf deletion in mouse models of T-ALL using ionizing radiation (IR)- or mutant Pten-, induced T-ALLs. In Aim 2 we will determine the molecular mechanisms underlying Hsf deletion in mouse models of T-ALL and will assess global transcriptional changes during T cell development in the presence or absence of hsfs and TP53 genes using RNA sequencing. Exome sequencing of HSCs following IR that will reveal profile mutations that are eliminated when Hsfs are deleted. In Aim 3 we will assess if the depletion of Hsfs from human or mouse primary tumors or T-ALL cell lines leads to tumor cell death.

急性淋巴细胞白血病（T-ALL）起源于T细胞谱系。疾病 每年占儿童ALL病例的15%和成人ALL病例的25%，使其成为最常见的 癌症在年轻人和老年人中。疾病经常复发， 80%以上的复发T-ALL病例携带TP 53突变。这些患者发展 对化疗的抵抗与非常差的预后相关。有的人总 进入缓解期的患者面临着严重的并发症， 积极的化疗因此，了解这些分子机制至关重要， 导致和驱动T-ALL，以发现具有更好特异性的新治疗靶点， 降低毒性。原发性和复发性T-ALL患者以及接受放射治疗的小鼠- 诱导的T-ALL具有非常高的活化Notch 1和TP 53突变的发生率。的确， TP 53缺陷型小鼠表现出70%的ALL发生率，这表明这是一个很好的模型， 研究T-ALL的生物学和分子机制。我们发现删除 热休克因子（Hsfs）Hsf 4、Hsf 2或Hsf 1在TP 53缺陷小鼠中导致显著的 防止T-ALL的发展。这些数据表明，Hsfs的治疗性抑制 可能是消灭T-ALL的关键在这项资助中，我们设计了一些研究来测试 在T-ALL小鼠模型中hsf缺失的研究，并跟踪从 从骨髓（BM）造血干细胞（HSC）到胸腺祖细胞再到成熟T细胞。 最后，我们将研究降低人类T-ALL细胞系中Hsf的表达水平， 体外培养原代肿瘤细胞或在T-ALL荷瘤小鼠中诱导缺失Hsfs将是一个很好的方法。 T-ALL的治疗选择。我们假设Hsfs不是T细胞增殖所必需的。 然而，它们与癌基因和肿瘤抑制基因合作， T-ALL的发展和Hsfs的耗竭导致T-ALL细胞无法存活。要求1 将确定Hsf缺失在使用电离辐射的T-ALL小鼠模型中的功效 (IR)-或突变Pten-诱导的T-ALL。在目标2中，我们将确定分子机制 T-ALL小鼠模型中潜在的Hsf缺失，并将评估整体转录 在存在或不存在hsfs和TP 53基因的情况下， RNA测序。IR后HSC的外显子组测序将揭示 当删除HSF时会消除。在目标3中，我们将评估从 人或小鼠原发性肿瘤或T-ALL细胞系导致肿瘤细胞死亡。