Role of heat shock factors (Hsfs) in tumorigenesis

描述（由申请人提供）：急性淋巴细胞白血病（T- all）起源于T细胞谱系。该疾病占每年儿科病例的15%和成人ALL病例的25%，使其成为非常年轻和老年人群中最常见的癌症。疾病复发频繁，超过80%的复发T-ALL病例携带TP53突变。这些患者对化疗产生耐药性，预后很差。此外，那些确实进入缓解期的患者由于先前的积极化疗而面临严重的并发症。因此，了解引起和驱动T-ALL的分子机制是至关重要的，以便发现具有更好特异性和降低毒性的新治疗靶点。原发性和复发性T-ALL患者以及放射诱导的T-ALL小鼠具有非常高的Notch1激活和TP53突变发生率。事实上，tp53缺陷小鼠的all发病率高达70%，这表明这是研究T-ALL生物学和分子机制的良好模型。我们发现tp53缺陷小鼠中缺失热休克因子（Hsfs） Hsf4、Hsf2或Hsf1可显著抑制T-ALL的发生。这些数据表明，治疗性抑制hsf可能是消除T-ALL的关键。在这项资助中，我们设计了一些研究来测试hsf缺失在T- all小鼠模型中的功效，并跟踪从骨髓（BM）造血干细胞（hsc）到胸腺祖细胞再到成熟T细胞的转录全基因组转移。最后，我们将研究体外降低人T-ALL细胞系和原代肿瘤细胞中的Hsf表达水平或诱导T-ALL小鼠中Hsf的缺失是否会成为治疗T-ALL的良好选择。我们假设hsf不是T细胞发育所必需的；然而，它们与癌基因和肿瘤抑制基因合作控制T-ALL的发展，Hsfs的耗尽导致T-ALL细胞无法存活。目的1将利用电离辐射（IR）或突变Pten诱导的T-ALL，确定Hsf缺失对小鼠T-ALL模型的疗效。在Aim 2中，我们将确定T- all小鼠模型中Hsf缺失的分子机制，并将使用RNA测序评估在存在或不存在Hsf和TP53基因的情况下T细胞发育过程中的全局转录变化。IR后hsc的外显子组测序将揭示当hsf被删除时被消除的谱突变。在目标3中，我们将评估从人类或小鼠原发肿瘤或T-ALL细胞系中消耗hsf是否会导致肿瘤细胞死亡。

DESCRIPTION (provided by applicant): 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.