(PQ5) Mitochondria in Leukemic Stem Cell Disease Progression

(PQ5) 白血病干细胞疾病进展中的线粒体

• 批准号: 9753161
• 负责人: SAGHI GHAFFARI
• 金额: $ 37.5万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9753161
• 关键词: Address; Blood; Cell Compartmentation; Cell Maintenance; Data; Disease; Disease Progression; Doxycycline; Drug resistance; Dysmyelopoietic Syndromes; Epigenetic Process; Event; Exhibits; FOXO3A gene; Failure; Flow Cytometry; Generations; Genetic; Genetic Transcription; Goals; Health; Hematologic Neoplasms; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Laboratories; Leukemic Cell; Maintenance; Matrix Metalloproteinases; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Molecular; Myeloproliferative disease; Pathway interactions; Phenotype; Play; Population; Process; Property; Regulation; Relapse; Stem cells; Testing; Transgenic Mice; base; cancer stem cell; conventional therapy; design; improved; leukemia; leukemic stem cell; mitochondrial metabolism; mortality; mouse model; novel; off-label use; prevent; stem cell biology; stem-like cell; success; targeted treatment; therapy resistant; transcription factor; transcriptome

ABSTRACT Conventional and targeted therapies have had little success in eradicating myeloid malignancies including in myeloproliferative neoplasms (MPNs). The inability to reliably prevent the generation of a small subset of drug-resistant stem cell-like leukemic cells (or leukemic stem cells (LSCs)) that cause relapse and the incapacity to target LSC has contributed to this failure. Mitochondrial metabolism has been implicated in regulating both LSC and hematopoietic stem cells (HSC) activity, however many other aspects of mitochondrial functions that contribute to the health of stem cell machinery remain largely unknown. We have discovered mitochondrial heterogeneity in a highly purified population of primitive HSC. Overall our results indicate that mitochondrial heterogeneity might subdivide stem cell compartment into fractions with distinct properties and activities. In addition, we have shown that the transcription factor FOXO3 that is required for both normal hematopoietic and leukemic stem cell maintenance is essential for HSC mitochondrial metabolism. Based on our studies and the similarities of normal blood-forming and leukemic stem cells, we propose to test the hypothesis that deregulated FOXO3 activity promotes the generation of pre-leukemic stem cells in the context of myeloid malignancies. We propose to test this hypothesis in a model of MPN that designate a group of blood clonal stem cell disorders that have the potential to progress to leukemia and in which metabolic/mitochondrial pathways have been broadly implicated. We will take advantage of mitochondrial heterogeneity to identify subpopulations of HSC and LSC with distinct stem cell properties and potential. Aim 1: To investigate functional consequences of Long-term-HSC mitochondrial heterogeneity; Aim 2: To elucidate the mechanism of FOXO3 regulation of mitochondria in stem cells. These studies are highly likely to improve our understanding of leukemic stem cell biology and the contribution of mitochondria to the LSC generation.

摘要 常规和靶向治疗在根除骨髓恶性肿瘤方面几乎没有成功 包括骨髓增生性肿瘤（MPN）。无法可靠地防止产生小的 耐药干细胞样白血病细胞（或白血病干细胞（LSC））的子集，其引起复发， 无法瞄准LSC是造成这一失败的原因之一。线粒体代谢与 调节LSC和造血干细胞（HSC）活性，然而， 线粒体的功能，有助于健康的干细胞机制仍然在很大程度上未知。我们 在高度纯化的原始HSC群体中发现了线粒体异质性。总体上我们的 结果表明，线粒体异质性可能将干细胞区室细分为具有以下特征的组分： 不同的属性和活动。此外，我们已经证明，转录因子FOXO 3， 造血干细胞和白血病干细胞的正常维持所必需的是HSC 线粒体代谢根据我们的研究和正常造血和白血病的相似性， 干细胞，我们建议测试这一假设，即失调FOXO 3活性促进的产生， 白血病前干细胞在骨髓恶性肿瘤的情况下。我们建议在一个 MPN模型，指定一组具有进展潜力的血液克隆干细胞疾病 代谢/线粒体途径已被广泛牵连。我们将采取 线粒体异质性在鉴别具有不同干细胞的HSC和LSC亚群中的优势 性能和潜力。目的1：研究长期HSC的功能后果 目的2：阐明FOXO 3调节线粒体异质性的机制， 干细胞中的线粒体这些研究极有可能提高我们对白血病干细胞的认识 细胞生物学以及线粒体对LSC产生的贡献。