Targeting leukemic stem cells in acute myeloid leukemia

项目摘要 急性髓性白血病（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）。这种肿瘤细胞的永生储库显示出极低的增殖率和对肿瘤细胞的抗性。 目前的治疗。它们也是复发的原因。制定有效的战略仍然是一项重大挑战， 治疗剂来根除LSC。一种新的方法，重点是独特的特点和脆弱性， 为了解决这一问题，需要地方供应链。我们之前发现了一种生物能应激诱导的 在研究PTPMT 1（一种线粒体- 磷酸肌醇磷酸酶。PTPMT 1的敲除降低线粒体代谢并导致 生物能应激，这反过来触发细胞周期检查点（AMPK-p21/p57），导致分化- 相关的细胞周期停滞。重要的是，这些基因敲除的HSC的存活和自我更新并不依赖于细胞的生长。 受影响，其分化阻滞是可逆的。我们最近的初步研究表明， 生物能应激诱导的细胞周期检查点也可能在LSC中起作用-LSC的发育和 维持癌基因（FLT 3-ITD和MLL-AF 9）驱动的或PTEN缺失诱导的AML基本上是 PTPMT 1的缺失抑制。有趣的是，PTPMT 1缺失诱导LSC中的细胞死亡， 与HSC相比。从机制上讲，PTPMT 1缺失不会影响线粒体结构;相反，它似乎会影响线粒体结构。 阻断线粒体对主要代谢底物丙酮酸（葡萄糖衍生的关键代谢物）的利用 位于线粒体氧化和胞质发酵的交叉点。根据这些观察， 我们假设可以通过诱导生物能量/代谢应激和细胞周期停滞来靶向LSC， 通过药理学抑制PTPMT 1或线粒体摄取丙酮酸，这产生了可能性， 消灭LSC的方法值得注意的是，阿来西定二盐酸盐，一种用作抗感染和抗斑块的抗生素， 已被确定为一种选择性和有效的PTPMT 1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），已显示有效抑制线粒体丙酮酸载体/转运蛋白（MPC）。因此，在本发明中， 这些药物的新特性将成为检验我们假设的关键资产。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）。为了进一步描述 LSC上的PTPMT 1耗竭。2）。为了确定PTPMT 1缺失抑制 线粒体代谢3）。检测PTPMT 1抑制剂阿来西定的潜在治疗作用 二盐酸盐和MPC抑制剂罗格列酮在人AML的异种移植模型中的作用。这个项目，如果 成功，可能导致一种新的策略，以消除AML中的LSC，PTPMT 1和MPC抑制剂可能是 重新利用并进一步开发成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.