Interrogation of the oxidative-stress-induced leukemia program in vivo using metabolic imaging

项目概要/摘要 急性髓性白血病（AML）是一种遗传复杂和异质性的疾病，其特征在于： 多种突变。虽然许多患者最初对治疗有反应，但许多人最终复发。来 近十年来，对AML的遗传多样性和克隆层次的认识为新的治疗方法打开了大门。 针对特定AML亚型的治疗靶点和治疗方法。此外，AML已被发现 具有独特的具有治疗意义的代谢特征。最重要的是， 异柠檬酸脱氢酶（IDH 1/2）已导致临床批准的药物。然而，许多患者成为 对这种疗法也有抗药性，进一步强调了对靶向失调的新策略的需要。 白血病的代谢通过开发新型微弹簧圈平台来探索白血病代谢 使用HP MR（Jeong等人，Science Advances 2017），我们已经确定了一种新的代谢脆弱性， 白血病的糖酵解代谢（Jeong et al. Cell Metabolism 2021）。这种对糖酵解代谢的依赖 不仅改变葡萄糖流向乳酸，还改变通过丝氨酸途径的一碳流量，这有助于葡萄糖的代谢。 谷氨酰胺代谢。此外，我们发现，基因靶向或抑制 一种通过该途径介导通量的酶（PHGDH）利用了这些细胞中新的脆弱性。 重要的是，这种靶向不会影响正常的造血细胞生长。在广泛的基础上， 我们的实验室和充足的初步数据之间的合作，我们的目标是采用创新的方法来研究 代谢（Keshari实验室），包括通过开发非侵入性探针来测量糖酵解的变化， 超极化磁共振成像的氧化应激。这种新陈代谢的特点是- 定义的AML模型（Kharas实验室），同时进行遗传和药理学调节，以开发一种 评估白血病干细胞驱动的AML代谢和丝氨酸代谢抑制的策略。 总之，这些研究将导致新的机制见解和新的癌症疗法。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a genetically complex and heterogeneous set of diseases characterized by a diverse set of mutations. Although many patients initially respond to treatment, many end up relapsing. Over the last decade, an appreciation of the genetic diversity and clonal hierarchy in AML has opened the door to novel therapeutic targets and therapeutic approaches to specific AML subtypes. Moreover, AML has been found to bear unique metabolic features with therapeutic implications. Most importantly, mutations in the enzymes isocitrate dehydrogenase (IDH1/2) have led to clinically approved drugs. However, many patients become resistant to this therapy as well, further underscoring the need for new strategies to target dysregulated metabolism in leukemia. Through the development of novel microcoil platforms to explore leukemia metabolism with HP MR (Jeong et al. Science Advances 2017) we have identified a new metabolic vulnerability in the glycolytic metabolism of leukemia (Jeong et al. Cell Metabolism 2021). This reliance on glycolytic metabolism alters not only glucose flux to lactate, but also one-carbon flux through the serine pathway, which facilitates the metabolism of glutamine. Moreover, we found that genetically targeting or pharmacologically inhibiting the enzyme that mediates flux through this pathway (PHGDH) capitalizes on a new vulnerability in these cells. Importantly, this targeting does not affect normal hematopoietic cell growth. Thus, building upon extensive collaboration between our labs and ample preliminary data, we aim to employ innovative approaches to study metabolism (Keshari Lab), including by developing non-invasive probes to measure changes in glycolysis and oxidative stress with hyperpolarized magnetic resonance imaging. This metabolism will be characterized in well- defined models of AML (Kharas Lab), with both genetic and pharmacological modulation, in order to develop a strategy to assess leukemia-stem-cell-driven AML metabolism and the inhibition of serine metabolism. Altogether, these studies will result in new mechanistic insights and novel cancer therapies.