Targeting metabolism in leukemic stem cells

描述（由申请人提供）：急性髓性白血病（AML）是一种克隆性血液系统恶性肿瘤，起源于并由一小群自我更新的前体细胞-白血病干细胞（LSCs）维持。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细胞，是由LSCs通过称为再群体/分化的过程产生的。白血病细胞迅速扩张，在多个器官引起毁灭性的病理影响。LSCs也是肿瘤转移、耐药和复发的主要来源。这种不朽的癌细胞储存库显示出极低的增殖率，目前的治疗方法可能无法根除。显然，需要一种专注于LSCs独特特性的新方法。我们最近的研究已经确定了PTPMT1（一种线粒体pten样磷脂酰亚脂磷酸酶）在胚胎干细胞（ESCs）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至关重要，因为在这一过程中能量需求迅速上升。PTPMT1耗竭会改变线粒体有氧代谢并引起生物能量应激，导致细胞周期改变，从而阻断ESCs和hsc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谱系造血祖细胞是必不可少的。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鉴定。

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.