Lysosomes and their Communications with Mitochondria in Leukemic Stem Cell Disease Progression

白血病干细胞疾病进展中的溶酶体及其与线粒体的通讯

• 批准号: 10522534
• 负责人: SAGHI GHAFFARI
• 金额: $ 40.14万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522534
• 关键词: Acute Myelocytic Leukemia; Adopted; Adult; Aging; Autophagocytosis; Biology; Blood; Cell Maintenance; Cell Separation; Cells; Cellular Metabolic Process; Clinical; Clonality; Communication; Disease Progression; Fostering; Functional disorder; Gene Targeting; Generations; Genomics; Glucose; Glycolysis; Goals; Hematopoietic Stem Cell subsets; Hematopoietic stem cells; Heterogeneity; Human; Image; Imaging Techniques; Link; Lysosomes; Maintenance; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Molecular; Mus; Myeloid Leukemia; Myeloproliferative disease; Nutrient; Organelles; Outcome; Pathogenesis; Patients; Population Heterogeneity; Preleukemia; Process; Property; Recurrence; Recycling; Regulation; Relapse; Resistance; Sampling; Testing; Time; Treatment Failure; Work; base; design; hematopoietic stem cell quiescence; high resolution imaging; improved; in vivo; leukemia; leukemic stem cell; leukemic transformation; mouse model; population based; preservation; stem cell division; stem cell population; stem cells; therapeutic target; therapy design; therapy outcome

PROJECT SUMMARY/ABSTRACT Leukemia therapy remains challenging and options are limited for a large fraction of patients who relapse. Growing evidence suggests that the therapy outcome and failure in myeloid leukemias are intimately linked to properties of leukemic stem cells (LSCs). Quiescence is a fundamental property shared between LSCs and normal hematopoietic stem cells (HSCs). Thus, targeting quiescent leukemic stem cells is essential for a successful long-lasting leukemia therapy. Achieving this goal requires identification of building blocks of stem cell quiescence and an in-depth understanding of mechanisms that wire them together. By exploiting mitochondrial heterogeneity we identified discrete deeply quiescent and potent subsets of mouse and human HSCs. This led us to our discovery that lysosomal activity is heterogeneous in HSCs and key in maintaining their quiescence. We find lysosomes retain damaged mitochondria and that they are critical to the maintenance of HSC quiescence and metabolism. We have extended these studies to myeloid leukemias, using both a mouse model of pre-leukemia and leukemia as well as leukemic patients’ samples and find that leukemic stem cell populations are heterogeneous distinctively in their lysosomal and mitochondrial properties. Based on our combined results we propose to investigate the implications of lysosomal heterogeneity for LSC isolation, generation and maintenance. In Aim 1, we will take advantage of combined lysosomal and mitochondrial heterogeneity to select LSCs subsets for further investigating their distinct function related to their lysosomal and mitochondrial alterations; in Aim 2, we will investigate the modulation of lysosomal-mediated metabolic pathways in LSC subsets; and in Aim 3, we will investigate the potential of dysregulated lysosomes in mediating the generation of pre-leukemic stem cells. Altogether these studies are likely to improve our approaches for isolating LSCs and our understanding of LSC generation and maintenance.

项目概要/摘要 白血病治疗仍然具有挑战性，对于很大一部分复发患者来说，选择是有限的。 越来越多的证据表明，髓系白血病的治疗结果和失败密切相关 白血病干细胞（LSC）的特性。静止是 LSC 之间共享的基本属性 和正常造血干细胞（HSC）。因此，靶向静止的白血病干细胞对于 成功的长期白血病治疗。实现这一目标需要识别干的构建模块 细胞静止以及对将它们连接在一起的机制的深入了解。通过利用 线粒体异质性，我们确定了小鼠和人类的离散深度静止和有效子集 HSC。这使我们发现 HSC 中的溶酶体活性是异质的，并且是维持 他们的安静。我们发现溶酶体保留受损的线粒体，并且它们对于 维持 HSC 的静止和代谢。我们已将这些研究扩展到骨髓性白血病， 使用白血病前期和白血病的小鼠模型以及白血病患者的样本，发现 白血病干细胞群在溶酶体和线粒体方面具有明显的异质性 特性。根据我们的综合结果，我们建议研究溶酶体的影响 LSC 分离、生成和维护的异质性。在目标 1 中，我们将利用综合优势 溶酶体和线粒体异质性来选择 LSC 子集以进一步研究其独特的 与其溶酶体和线粒体改变相关的功能；在目标 2 中，我们将研究调制 LSC 亚群中溶酶体介导的代谢途径；在目标 3 中，我们将研究以下方面的潜力： 溶酶体失调介导白血病前干细胞的生成。这些研究总共是 可能会改善我们分离 LSC 的方法以及我们对 LSC 生成和的理解 维护。