Targeting metabolism in leukemic stem cells

描述(申请人提供)：急性髓系白血病(AML)是一种克隆性血液系统恶性肿瘤，起源于一小部分自我更新的前体细胞-白血病干细胞(LSCs)，并由其持续存在。这种疾病是由一个等级系统组织的，其中大部分白血病细胞，即处于不同成熟阶段的原始细胞，是由LSC通过称为再繁殖/分化的过程产生的。在这里，白血病母细胞迅速扩张，并在多个器官引起毁灭性的病理效应。LSCs也是肿瘤转移、耐药和复发的主要来源。这种不朽的癌细胞库表现出极低的增殖率，很可能不会被目前的治疗方法根除。显然，需要一种新的方法来关注LSC的独特性质。我们最近的研究确定了PTPMT1在胚胎干细胞(ESCs)和造血干细胞(HSCs)分化中的关键作用。PTPMT1是一种线粒体PTEN样磷酸肌醇磷脂磷酸酶。这种磷酸酶对于从糖酵解到线粒体氧化磷酸化的代谢转变是必不可少的，这是ESC和HSC分化所需的，因为在这个过程中能量需求迅速上升。PTPMT1缺失改变线粒体的有氧代谢，引起生物能量应激，导致细胞周期改变，从而阻止ESCs和HSCs的分化(不影响细胞存活)。有趣的是，PTPMT1对于分化的胚胎成纤维细胞和血统定向的造血祖细胞来说是必不可少的。这些研究导致了由生物能量应激激活的干细胞特异性分化检查点的确定。 由于LSCs具有与正常HSC相同的某些特性，包括分化过程中的代谢重编程，我们假设PTPMT1在LSCs进入原始阶段的过程中发挥着类似的重要作用，并且LSC的分化/再繁殖能力可以通过抑制PTPMT1激活能量应激诱导的分化检查点而被阻断。我们计划通过追求两个目标来检验我们的假设，并实现本应用的目标。1)。目的：探讨PTPMT1在LSC分化/再分化中的作用。2)。目的：检测PTPMT1抑制剂在AML异种移植模型中的治疗效果。这项应用测试了一种新的想法，即通过诱导代谢应激来阻断LSC的功能，这代表了一种潜在控制AML的创新方法。此外，由于将要测试的PTPMT1选择性抑制剂也是一种已知的抗生素，这项工作可能会导致发现一种新的治疗药物，在LSCs中诱导分化阻断，从而防止AML白血病原始细胞的形成。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML), a clonal hematological malignancy, originates from and is sustained by a small population of self-renewing precursor cells - leukemic stem cells (LSCs). This disease is organized by a hierarchy system where the bulk of leukemic cells, i.e. blasts at various stages of maturation, are generated from LSCs through the process known as repopulation/differentiation. Here, leukemic blasts are rapidly expanded and evoke devastating pathological effects in multiple organs. LSCs are also the major source for metastasis, drug resistance, and relapse of the disease. This immortal reservoir of cancer cells display extremely low proliferation rates and likely are not eradicated by current treatments. Clearly, a novel approach focused on the unique properties of LSCs is needed. Our recent studies have established a critical role of PTPMT1, a mitochondrial PTEN-like phosphotidylinositide phosphate phosphatase, in differentiation of embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs). This phosphatase is essential for the metabolic transition from glycolysis to mitochondrial oxidative phosphorylation required for ESC and HSC differentiation, owing to the quickly rising energy demand during this process. PTPMT1 depletion alters mitochondrial aerobic metabolism and causes bioenergetic stress, leading to cell cycle changes and thus a differentiation block in ESCs and HSCs (without affecting cell survival). Intriguingly, PTPMT1 is dispensable for differentiated embryonic fibroblasts and lineage-committed hematopoietic progenitors. These studies led to the identification of a stem cell-specific differentiation checkpoint activated by bioenergetic stress. As LSCs share certain properties with normal HSCs, including metabolic reprogramming during differentiation, we hypothesize that PTPMT1 plays a similarly important role in the progression of LSCs to the blast stage and that LSC differentiation/repopulation capabilities can be blocked via activation of the energetic stress-induced differentiation checkpoint through inhibition of PTPMT1. We plan to test our hypothesis and accomplish the objective of this application by pursuing two aims. 1). To determine the role of PTPMT1 in LSC differentiation/repopulation. 2). To test for the therapeutic effects of a PTPMT1 inhibitor in the AML xenograft model. This application tests a novel idea, i.e. blocking LSC function by inducing metabolic stress, which represents an innovative approach to potentially control AML. In addition, as the PTPMT1 selective inhibitor to be tested is also a known antibiotic, this work may lead to the identificatin of a new therapeutic agent in eliciting a differentiation block in LSCs, thus preventing leukemic blast formation in AML.