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: 10688239
• 负责人: SAGHI GHAFFARI
• 金额: $ 39.33万
• 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/10688239
• 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; Repression; Resistance; Sampling; Testing; Time; Treatment Failure; Work; design; hematopoietic stem cell quiescence; high resolution imaging; improved; in vivo; leukemia; leukemia treatment; leukemic stem cell; leukemic transformation; molecular dynamics; mouse model; preservation; stem; 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.

项目摘要/摘要 白血病疗法仍然面临挑战，对于中继的大量患者，选择量受到限制。 越来越多的证据表明，髓样白血病的治疗结果和失败是密切联系的 白血病细胞（LSC）的性质。静止是LSC之间共有的基本属性 和正常的造血干细胞（HSC）。那就是靶向静态白血病干细胞对于 成功的长期白血病疗法。实现此目标需要识别STEM的构件 细胞的静止和对将它们连接在一起的机制的深入理解。通过利用 线粒体异质性我们确定了小鼠和人类的离散静止和潜在子集 HSC。这使我们发现溶酶体活性在HSC中是异质的，并且保持关键 他们的静止。我们发现溶酶体保留了受损的线粒体，它们对 维持HSC静止和代谢。我们已经将这些研究扩展到髓样白血病， 同时使用美质前和白血病的小鼠模型以及白血病患者的样本，发现 白血病干细胞种群在其溶酶体和线粒体中独特的异质性是异质的 特性。根据我们的综合结果，我们建议研究溶酶体的含义 LSC隔离，生成和维护的异质性。在AIM 1中，我们将利用合并 溶酶体和线粒体异质性选择LSCS子集，以进一步研究其独特的 与它们的溶酶体和线粒体改变有关的功能；在AIM 2中，我们将调查调制 LSC子集中的溶酶体介导的代谢途径；在AIM 3中，我们将研究 在介导白血病前干细胞产生时，溶酶体失调。这些研究完全是 可能会改善我们隔离LSC的方法以及我们对LSC生成的理解和 维护。