Heat Shock Transcription Factor 1 Specifically Regulates AML Stem Cell Self-Renewal

热休克转录因子 1 特异性调节 AML 干细胞自我更新

• 批准号: 10414821
• 负责人: Chen Zhao
• 金额: $ 39.66万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10414821
• 关键词: Ablation; Acute Myelocytic Leukemia; Affect; Apoptosis; Biology; Biopsy Specimen; Bone Marrow Cells; Bone marrow biopsy; CD34 gene; Cells; ChIP-seq; Chromatin; Clinical Markers; DNA metabolism; Data; Defect; Development; Diffuse; Dysmyelopoietic Syndromes; Energy Metabolism; Epigenetic Process; Epithelial Cells; Feedback; Frequencies; Gene Expression; Genes; Genetic Transcription; Growth; Heat shock proteins; Hematopoiesis; Hematopoietic stem cells; Homeostasis; Human; Impairment; Knowledge; Leukemic Cell; Liver; Lymphoblastic Leukemia; MLL-AF9; Maintenance; Malignant - descriptor; Minority; Mitochondria; Modeling; Molecular; Monitor; Mus; Mutate; Myeloproliferative disease; Oncogenes; Outcome; Oxidative Phosphorylation; Pathway interactions; Patients; Play; Proteins; Relapse; Research; Role; Signal Transduction; Signaling Molecule; Solid Neoplasm; Stress; Testing; acute myeloid leukemia cell; amino acid metabolism; base; cancer cell; cell injury; chemotherapy; clinically relevant; experience; genetic manipulation; glucose metabolism; heat shock transcription factor; hepatocyte nuclear factor; improved; intestinal epithelium; leukemia; leukemic stem cell; misfolded protein; overexpression; protein metabolism; proteotoxicity; reconstitution; self-renewal; small molecule; small molecule inhibitor; stem cell function; stem cell proliferation; stem cell self renewal; stemness; success; therapeutic target; transcription factor; transcriptomics; treatment effect; treatment response; tumorigenesis

Project Summary/Abstract Acute myeloid leukemia (AML) is maintained by a small minority of self-renewing leukemic stem cells (LSCs). Defining and targeting the key molecules that specifically regulate LSCs might eradicate AML. Heat shock transcription factor 1 (HSF1) is known to regulate the expression of heat shock proteins (HSPs) to protect cells from misfolded protein-induced proteotoxic stress. Although HSF1 is not an oncogene, it enables cancer cells to accommodate imbalances in signaling and alterations in DNA, protein, and energy metabolism, a phenomenon called “non-oncogene addiction”. Targeting HSPs in AML is being explored with promising results. However, targeting HSPs induces feedback that increases HSF1 activity, which may compromise treatment effects. Therefore, targeting HSF1 directly may be a more attractive alternative. However, given the critical roles of HSF1 in the maintenance of normal cellular homeostasis, targeting HSF1 could adversely affect normal hematopoiesis. Unexpectedly, our preliminary data show that HSF1 is dispensable for normal hematopoiesis, but specifically required for the self-renewal of LSCs. Mechanistically, deletion of HSF1 disrupts amino acid metabolism and mitochondrial oxidative phosphorylation (OXPHOS), which plays a critical role in regulating LSC function, and dysregulates multifaceted genes involved in LSC stemness. In addition, we identified that hepatocyte nuclear factor 4a (HNF4a) as a direct HSF1 target. Overexpression of HNF4a largely reconstitutes deletion of HSF1-induced impaired LSC function. Based on these observations, we hypothesize that HSF1 is specifically required for LSC self-renewal through regulating leukemic energy metabolism (mainly OXPHOS) and is a potential therapeutic target in AML. We propose the following two specific aims to test our hypothesis. Aim 1: To determine the underlying mechanism whereby HSF1 is specifically required for LSC self-renewal. We will determine 1) the impact of HSF1 ablation on LSC frequencies, proliferation and OXPHOS; 2) the HSF1 transcriptional targets in LSCs by comprehensive analysis of transcriptomic gene expression, chromatin accessibility and chromatin immunoprecipitation (ChIP) sequencing in the presence or absence of HSF1; 3) how HNF4a reconstitutes HSF1 ablation-induced LSC defects, especially the effect of HNF4a on OXPHOS; and 4) if deletion of HSF1 impairs mechanistically different types of AML. Aim 2: To determine if targeting HSF1 effectively eliminate human LSCs. We will determine 1) the impact of HSF1 inhibition on human LSC proliferation, apoptosis, self-renewal and oxidative phosphorylation; 2) the HSF1- dependent regulatory circuitry in human LSCs; and 3) if the expression of HSF1 protein correlates with AML therapeutic response and relapse. The expected outcomes of this comprehensive analysis are identification of the mechanism whereby HSF1 specifically regulates LSC self-renewal, providing the rationale for targeting HSF1 and using HSF1 to monitor AML progression.

项目总结/文摘