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

项目摘要/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，选择有限。 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(LSCs)的特性。静止状态是LSC之间共享的基本属性 和正常造血干细胞(HSCs)。因此，靶向静止的白血病干细胞对于 成功的长效白血病治疗。实现这一目标需要确定茎的构建块 细胞静止，并深入了解将它们连接在一起的机制。通过剥削 线粒体异质性我们确定了小鼠和人的离散的、深度静止的和有效的亚群 造血干细胞。这导致我们发现，在造血干细胞中，溶酶体的活性是不同的，并且是维持 他们的宁静。我们发现溶酶体保留了受损的线粒体，并且它们对 维持HSC的静止和新陈代谢。我们已经将这些研究扩展到髓系白血病， 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 白血病干细胞群体在溶酶体和线粒体上具有明显的异质性 属性。基于我们的综合结果，我们建议研究溶酶体的含义。 LSC分离、生成和维护的异构性。在目标1中，我们将利用联合 溶酶体和线粒体异质性筛选LSCs亚群以进一步研究其差异 与其溶酶体和线粒体改变相关的功能；在目标2中，我们将研究其调节 溶酶体介导的代谢途径在LSC亚群中的作用；在目标3中，我们将研究 调节失调的溶酶体在白血病前期干细胞生成中的作用。总而言之，这些研究是 可能会改进我们分离LSC的方法，以及我们对LSC生成和 维修。

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.