(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髓系恶性肿瘤方面收效甚微。 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亚群(或白血病干细胞(LSCs))，可导致复发和 无法瞄准LSC是导致这一失败的原因之一。线粒体新陈代谢被认为与 同时调节LSC和造血干细胞(HSC)的活性，但许多其他方面 有助于干细胞机器健康的线粒体功能在很大程度上仍不为人所知。我们 在高度纯化的原始HSC群体中发现了线粒体的异质性。整体来说，我们 结果表明，线粒体的异质性可能会将干细胞隔室细分为具有 不同的属性和活动。此外，我们已经证明了转录因子FOX03，即 对于正常的造血和白血病干细胞的维持是必不可少的 线粒体代谢。根据我们的研究和正常造血与白血病的相似性 干细胞，我们建议检验这样的假设，即解除调控的FOXO_3活性促进了 髓系恶性肿瘤背景下的白血病前干细胞。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性干细胞疾病 与白血病有关，代谢/线粒体途径被广泛牵涉其中。我们会带上 利用线粒体异质性鉴定干细胞不同亚群的优势 特性和潜力。目的1：研究长期高血压性肝星状细胞的功能后果 目的2：阐明FOXO_3对线粒体异质性的调控机制。 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理解。 细胞生物学和线粒体对LSC生成的贡献。