(PQ5) Mitochondria in Leukemic Stem Cell Disease Progression

(PQ5) 白血病干细胞疾病进展中的线粒体

基本信息

批准号：
9172951
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
项目类别：
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/9172951
关键词：
Address Blood Blood typing procedure Cell Maintenance Data Disease Disease Progression Doxycycline Drug resistance Dysmyelopoietic Syndromes Epigenetic Process Event Exhibits FOXO3A gene Failure Flow Cytometry Generations Genetic Goals Health Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Heterogeneity Label Laboratories Leukemic Cell Leukemic Hematopoietic Stem 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 blood group cancer stem cell conventional therapy design improved leukemia leukemic stem cell mitochondrial metabolism mortality mouse model novel prevent stem stem cell biology success targeted treatment therapy resistant transcription factor transcriptome

Address Blood Blood typing procedure Cell Maintenance Data Disease Disease Progression Doxycycline Drug resistance Dysmyelopoietic Syndromes Epigenetic Process Event Exhibits FOXO3A gene Failure Flow Cytometry Generations Genetic Goals Health Hematologic Neoplasms Hematopoietic Hematopoietic stem cells Heterogeneity Label Laboratories Leukemic Cell Leukemic Hematopoietic Stem 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 blood group cancer stem cell conventional therapy design improved leukemia leukemic stem cell mitochondrial metabolism mortality mouse model novel prevent stem stem cell biology success targeted treatment therapy resistant transcription factor transcriptome

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项目摘要

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.

抽象的传统和靶向疗法在消除髓样恶性肿瘤方面几乎没有成功包括骨髓增生性肿瘤（MPN）。无法可靠防止产生小的导致复发和目标LSC的无能力导致了这一失败。线粒体代谢已与调节LSC和造血干细胞（HSC）活性，但是有助于干细胞机械健康的线粒体功能在很大程度上尚不清楚。我们在高度纯化的原始HSC种群中发现了线粒体异质性。总体而言结果表明，线粒体异质性可能会将干细胞室分成分数不同的特性和活动。此外，我们已经证明了转录因子FOXO3是正常造血和白血病干细胞维持所必需的对HSC必不可少线粒体代谢。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，我们建议检验以下假设，即失控的FOXO3活性促进了生成在髓样恶性肿瘤的背景下，白血病前干细胞。我们建议在指定有可能进步的血液克隆干细胞疾病的MPN模型白血病和代谢/线粒体途径已广泛涉及。我们会接受的线粒体异质性的优势以鉴定具有不同干细胞的HSC和LSC的亚群特性和潜力。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茎的理解细胞生物学和线粒体对LSC生成的贡献。