Targeting metabolism in leukemic stem cells

描述（由申请人提供）：急性髓性白血病（AML）是一种克隆性恶性血液病，起源于一小群自我更新的前体细胞-白血病干细胞（LSC）并由其维持。这种疾病是由一个层次系统组织的，其中大量的白血病细胞，即处于不同成熟阶段的原始细胞，通过称为再增殖/分化的过程从LSC产生。在这里，白血病原始细胞迅速扩大，并在多个器官引起破坏性的病理影响。LSC也是转移、耐药性和疾病复发的主要来源。这种永生的癌细胞库显示出极低的增殖率，并且可能无法通过目前的治疗根除。显然，需要一种专注于LSC独特特性的新方法。我们最近的研究已经确定了PTPMT 1，一种线粒体PTEN样磷脂酰肌醇磷酸酶，在胚胎干细胞（ESC）和造血干细胞（HSC）分化中的关键作用。这种磷酸酶对于ESC和HSC分化所需的从糖酵解到线粒体氧化磷酸化的代谢转变是必不可少的，这是由于在此过程中能量需求迅速增加。PTPMT 1耗竭改变线粒体有氧代谢并引起生物能应激，导致细胞周期变化，从而阻断ESC和HSC的分化（而不影响细胞存活）。有趣的是，PTPMT 1是分化的胚胎成纤维细胞和谱系定向造血祖细胞的标志。这些研究导致了干细胞特异性分化检查点的鉴定，该检查点由生物能量应激激活。 由于LSC与正常HSC具有某些特性，包括分化过程中的代谢重编程，我们假设PTPMT 1在LSC向胚细胞阶段的进展中起着类似的重要作用，并且LSC分化/再增殖能力可以通过抑制PTPMT 1激活能量应激诱导的分化检查点来阻断。我们计划通过追求两个目标来测试我们的假设并实现本申请的目标。1）。确定PTPMT 1在LSC分化/再增殖中的作用。2）。检测PTPMT 1抑制剂在AML异种移植模型中的治疗作用。该应用测试了一种新的想法，即通过诱导代谢应激来阻断LSC功能，这代表了潜在控制AML的创新方法。此外，由于待测试的PTPMT 1选择性抑制剂也是已知的抗生素，因此这项工作可能导致鉴定出一种新的治疗剂，其在LSC中引发分化阻滞，从而防止AML中白血病母细胞的形成。

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.