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 代表儿科的15％，每年有25％的成人案例，使其成为最常见的 年轻和老年人的癌症。疾病复发经常发生，更多 超过80％的复发T-所有病例具有TP53突变。这些患者发展 对化学疗法的抵抗力与预后较差有关。此外，那些 由于其先前，遭受缓解的患者面临严重的并发症 积极的化学疗法。因此，了解分子机制至关重要 原因和驱动T-all，以发现具有更好特异性的新型治疗靶标 毒性降低。原发性和复发T-alls以及带辐射的小鼠的患者 诱导的T-ALL具有很高的活化Notch1和TP53突变的发生率。的确， TP53缺乏的小鼠表现出70％的出现率，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 TP53缺陷小鼠中的热休克因子（HSF）HSF4，HSF2或HSF1导致显着 防止T-all的发展。这些数据表明治疗性抑制HSF 可能是消除T-all的关键。在这笔赠款中，我们设计了研究以测试功效 T-ALL小鼠模型中的HSF缺失的脑袋，并跟踪转录的全基因组转移 骨髓（BM）血体干细胞（HSC）至成熟T细胞的胸腺祖细胞。 最后，我们将研究是否降低了人类T-ALL细胞系中的HSF表达水平，并且 HSF在T-All Baberearth小鼠中的体外或可诱导缺失的原发性肿瘤细胞将是一个很好的 T-alls的治疗选择。我们假设HSF对于T细胞不是必不可少的 发展;但是，他们与癌基因和肿瘤抑制基因合作以控制 T-ALL发育和HSF的耗竭导致T-All细胞无法生存。目标1 将使用电离辐射确定HSF缺失在T-ALL小鼠模型中的功效 （ir）或突变体诱导的t-alls。在AIM 2中，我们将确定分子机制 T-ALL小鼠模型中的基本HSF缺失，并将评估全局转录 在存在或不存在HSF和TP53基因的情况下，T细胞发育过程中的变化 RNA测序。 IR之后的HSC的外显子组测序将揭示轮廓突变 删除HSF时将消除。在AIM 3中，我们将评估HSF的耗竭。 人或小鼠原发性肿瘤或T-ALL细胞系导致肿瘤细胞死亡。