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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘