Targeting leukemic stem cells in acute myeloid leukemia

项目概要 急性髓系白血病（AML）是一种克隆性血液恶性肿瘤，治疗选择有限。它 起源于一小群自我更新的前体细胞并由其维持 - 白血病起始/干细胞 细胞（LSC）。这种不朽的肿瘤细胞库表现出极低的增殖率和耐药性 目前的治疗方法。他们也对复发负有责任。开发有效的方法仍然是一个严峻的挑战 根除 LSC 的治疗方法。一种专注于独特特征和脆弱性的新颖方法 为了解决这个问题，需要 LSC。我们之前发现了一种生物能应激诱导的 研究 PTPMT1（一种线粒体）中造血干细胞 (HSC) 的分化/再增殖检查点 基于磷酸肌醇的磷酸酶。 PTPMT1 的敲除会降低线粒体代谢并导致 生物能应激，进而触发细胞周期检查点（AMPK-p21/p57），导致分化- HSC 中相关的细胞周期停滞。重要的是，这些敲除 HSC 的存活和自我更新并不 受影响，并且它们的分化障碍是可逆的。我们最近的初步研究表明，类似的 生物能应激诱导的细胞周期检查点也可能在 LSC 中发挥作用——发育和 癌基因（FLT3-ITD 和 MLL-AF9）驱动或 PTEN 缺失诱导的 AML 的维持基本上 PTPMT1 的缺失可抑制该作用。有趣的是，PTPMT1 缺失会诱导 LSC 中的细胞死亡， 与 HSC 相比。从机制上讲，PTPMT1 丢失不会影响线粒体结构；相反，它似乎 阻止线粒体利用主要代谢底物丙酮酸，这是一种源自葡萄糖的关键代谢物 它位于线粒体氧化和胞质发酵的交叉点。根据这些观察， 我们假设 LSC 可以通过诱导生物能/代谢应激和细胞周期停滞来靶向 通过药理学抑制 PTPMT1 或线粒体摄取丙酮酸，这产生了可能性 根除 LSC。值得注意的是，阿来西定二盐酸盐，一种用作防腐剂和抗牙菌斑的抗生素 用于牙科产品的药剂，已被确定为选择性且有效的 PTPMT1 抑制剂，罗格列酮 （文迪雅），一种可行的抗 2 型糖尿病药物（以前称为过氧化物酶体增殖物激活受体 γ 激动剂），已被证明可以有效抑制线粒体丙酮酸载体/转运蛋白（MPC）。结果， 这些药物的新颖特性将成为检验我们假设的重要资产。我们计划实现 通过追求以下三个目标来实现本提案的目标。 1）。为了进一步表征效果 LSC 上的 PTPMT1 耗尽。 2）。确定 PTPMT1 耗竭抑制的分子机制 线粒体代谢。 3）。测试 PTPMT1 抑制剂 alexidine 的潜在治疗效果 二盐酸盐和 MPC 抑制剂罗格列酮在人类 AML 异种移植模型中的作用。这个项目如果 成功，可能会导致一种在 AML 中消耗 LSC 的新策略，并且 PTPMT1 和 MPC 抑制剂可能是 重新利用并进一步开发为 AML 的治疗剂。

Project Summary Acute myeloid leukemia (AML) is a clonal hematological malignancy with limited therapeutic options. It originates from and is sustained by a small population of self-renewing precursor cells - leukemia initiating/stem cells (LSCs). This immortal reservoir of tumor cells displays extremely low proliferation rates and resistance to current treatments. They are also responsible for relapses. It remains a critical challenge to develop effective therapeutics to eradicate LSCs. A novel approach focused on the unique characteristics and vulnerabilities of LSCs is needed in order to address this problem. We previously discovered a bioenergetic stress-induced differentiation/repopulation checkpoint in hematopoietic stem cells (HSCs) in studying PTPMT1, a mitochondria- based phosphoinositide phosphatase. Knockout of PTPMT1 decreases mitochondrial metabolism and causes bioenergetic stress, which in turn triggers a cell cycle checkpoint (AMPK-p21/p57), leading to differentiation- associated cell cycle arrest in HSCs. Importantly, the survival and self-renewal of these knockout HSCs are not affected, and their differentiation block is reversible. Our recent preliminary study suggests that a similar bioenergetic stress-induced cell cycle checkpoint may also operate in LSCs --- the development and maintenance of oncogene (FLT3-ITD and MLL-AF9)-driven or PTEN loss-induced AML are substantially inhibited by the deletion of PTPMT1. Interestingly, PTPMT1 depletion induces cell death in LSCs, in sharp contrast to HSCs. Mechanistically, PTPMT1 loss does not impact mitochondrial structure; rather, it appears to block mitochondrial utilization of the major metabolic substrate pyruvate, a key metabolite derived from glucose that lies at the intersection of mitochondrial oxidation and cytosolic fermentation. Based on these observations, we hypothesize that LSCs can be targeted by inducing bioenergetic/metabolic stress and cell cycle arrest through pharmacological inhibition of PTPMT1 or mitochondrial uptake of pyruvate, which yields the possibility of eradicating LSCs. Notably, alexidine dihydrochloride, an antibiotic used as an anti-septic and anti-plaque agent for dental products, has been identified as a selective and potent PTPMT1 inhibitor, and rosiglitazone (Avandia), a viable anti-type 2 diabetic drug (previously known as a peroxisome proliferator-activated receptor γ agonist), has been shown to effectively inhibit the mitochondrial pyruvate carrier/transporter (MPC). As a result, the novel properties of these drugs will serve as a critical asset for testing our hypothesis. We plan to achieve the objective of this proposal by pursuing the following three aims. 1). To further characterize the effects of PTPMT1 depletion on LSCs. 2). To determine the molecular mechanisms by which PTPMT1 depletion inhibits mitochondrial metabolism. 3). To test for the potential therapeutic effects of the PTPMT1 inhibitor alexidine dihydrochloride and the MPC inhibitor rosiglitazone in xenograft models of human AML. This project, if successful, may lead to a novel strategy to deplete LSCs in AML, and the PTPMT1 and MPC inhibitors could be repurposed and further developed into therapeutic agents for AML.