Role of heat shock factors (Hsfs) in tumorigenesis

急性淋巴细胞白血病(T-ALL)起源于T细胞系。这种病 每年占儿科病例的15%和成人所有病例的25%，使其成为最常见的 癌症发生在非常年轻和年老的人群中。疾病复发频繁，而且更多 80%以上的复发性T-ALL患者存在TP53突变。这些患者会发展成 对化疗的抗药性与预后非常差有关。此外，那些 真正进入缓解期的患者将面临严重的并发症，因为他们之前 激进的化疗。因此，了解分子机制是至关重要的。 引起和推动T-ALL，以发现具有更好特异性和 降低了毒性。初发和复发T-ALL的患者以及接受辐射的小鼠- 诱导的T-ALL具有很高的Notch1激活和TP53突变的发生率。的确， TP53基因缺陷的小鼠表现出70%的ALL发生率，这表明这是一个很好的模型 探讨T-ALL的生物学和分子机制。我们发现删除了 热休克因子(Hsf)在TP53缺陷小鼠中的HSF4、Hsf2或HSF1导致显著 预防T-ALL的发展。这些数据表明，对Hsf的治疗抑制 可能是消灭T-ALL的关键。在这笔赠款中，我们设计了测试疗效的研究 T-ALL小鼠模型中HSF缺失的情况，并跟踪全基因组转录从 从骨髓(BM)造血干细胞(HSCs)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细胞株和 在体外培养原代肿瘤细胞或在T-ALL小鼠中诱导Hsf的缺失将是一个很好的选择 T-ALL的治疗选择。我们假设Hsf对T细胞不是必需的 发展；然而，它们与癌基因和肿瘤抑制基因合作控制 T-ALL的发育和Hsf的耗尽导致T-ALL细胞不能存活。目标1 将确定在使用电离辐射的T-ALL小鼠模型中HSF缺失的效果 (IR)-或突变体Pten-，诱导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，并将评估全局转录 有无hsf和tp53基因时T细胞发育过程中的变化 RNA测序。IR后HSCs的外显子组测序将揭示 在删除Hsf时被消除。在目标3中，我们将评估从 人或小鼠原发肿瘤或T-ALL细胞系可导致肿瘤细胞死亡。

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.