(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: 9336279
• 负责人: SAGHI GHAFFARI
• 金额: $ 38.66万
• 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/9336279
• 关键词: Address; Blood; Cell Compartmentation; Cell Maintenance; Cellular biology; 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; Label; Laboratories; Leukemic Cell; Maintenance; Metabolic; Metabolism; Mitochondria; Modeling; Modification; Molecular; Myeloproliferative disease; Pathway interactions; Phenotype; Play; Population; Process; Property; Regulation; Relapse; Stem cells; Testing; Transgenic Mice; base; blood group; cancer stem cell; conventional therapy; design; improved; leukemia; leukemic stem cell; mitochondrial metabolism; mortality; mouse model; novel; prevent; 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.

抽象的 传统疗法和靶向疗法在根除骨髓恶性肿瘤方面收效甚微 包括骨髓增生性肿瘤（MPN）。无法可靠地防止小颗粒的产生 耐药干细胞样白血病细胞（或白血病干细胞 (LSC)）的子集，可导致复发和 无法瞄准 LSC 是导致这次失败的原因。线粒体代谢与 调节 LSC 和造血干细胞 (HSC) 活性，但是许多其他方面 有助于干细胞机器健康的线粒体功能在很大程度上仍然未知。我们 在高度纯化的原始 HSC 群体中发现了线粒体异质性。总的来说我们的 结果表明，线粒体异质性可能将干细胞区室细分为以下几个部分： 独特的属性和活动。此外，我们还发现转录因子 FOXO3 正常造血干细胞和白血病干细胞维持所需的对 HSC 至关重要 线粒体代谢。根据我们的研究以及正常血液形成和白血病的相似性 干细胞中，我们建议检验 FOXO3 活性失调会促进干细胞生成的假设 骨髓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，指定一组有可能进展的血液克隆干细胞疾病 白血病，其中代谢/线粒体途径已被广泛涉及。我们将采取 利用线粒体异质性鉴定具有不同干细胞的 HSC 和 LSC 亚群 属性和潜力。目标 1：研究长期 HSC 的功能后果 线粒体异质性；目标2：阐明FOXO3调节的机制 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 细胞生物学和线粒体对 LSC 产生的贡献。