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。这种疾病