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

项目摘要/摘要 急性髓系白血病(AML)是一组基因复杂和异质性的疾病，其特征是 不同的突变集合。尽管许多患者最初对治疗有反应，但许多人最终复发。超过了 在过去的十年里，对急性髓系白血病遗传多样性和克隆层级的欣赏打开了小说的大门 针对特定AML亚型的治疗靶点和治疗方法。此外，急性髓系白血病已被发现 具有独特的代谢特征，具有治疗意义。最重要的是，酶的突变 异柠檬酸脱氢酶(IDH1/2)导致了临床批准的药物。然而，许多患者变成了 对这种疗法也有抵抗力，进一步强调了针对调控失调的新策略的必要性 白血病的新陈代谢。通过开发新型微线圈平台来探索白血病的代谢 与HP MR(Jeong et al.科学进步2017)我们发现了一种新的代谢脆弱性 白血病的糖酵解代谢(Jeong等人)。细胞新陈代谢2021)。这种对糖酵解代谢的依赖 不仅改变葡萄糖到乳酸的流量，还改变通过丝氨酸途径的一碳流量，这有助于 谷氨酰胺的代谢。此外，我们发现，通过基因靶向或药物抑制 通过这一途径调节流量的酶(PHGDH)利用了这些细胞中的一个新的脆弱性。 重要的是，这种靶向不会影响正常的造血细胞生长。因此，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 Lab)，包括通过开发非侵入性探针来测量糖酵解和 氧化应激与超极化磁共振成像。这种新陈代谢将在很好的- 已定义的AML模型(Kharas Lab)，具有遗传和药物调节，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，这些研究将带来新的机制洞察力和新的癌症疗法。

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.