METABOLIC REGULATION IN LEUKEMIA-INITIATING CELLS

急性髓系白血病是成人最常见的急性白血病，且随年龄增长而增多。尽管总体上 白血病治疗的进步，急性髓细胞白血病对老年患者的预后仍然是毁灭性的(更少 超过10%的患者存活5年)。因此，治疗AML的新疗法是必要的。AMPK是一种代谢 促进分解代谢和抑制合成代谢的调节剂，从而维持代谢动态平衡 代谢压力。使用小鼠模型和AMPK抑制剂，我们证明了AMPK抑制呈现 急性髓细胞白血病对饮食限制引起的代谢应激敏感(Saito等人)。干细胞。2015年)。在此期间 研究中，我们注意到AMPK缺失减少了AML中的乙酰辅酶A和组蛋白乙酰化(图2)，伴随而来 Myc等促进白血病的关键基因表达减少。重要的是，染色质 免疫沉淀和测序(CHIP-SEQ)显示AMPK缺失减少了 乙酰化组蛋白，所有这些都标记了活性基因，并招募了转录调节者。因此，我们 假设AMPK通过维持组蛋白乙酰化将AML的新陈代谢与表观遗传学联系起来。在目标1中，我们 将决定转录调控因子在AML中的占据是否受AMPK的调控。在目标2中，我们 将决定代谢物和产生乙酰辅酶A的代谢酶如何调节组蛋白 乙酰化。在目标3中，我们将确定AMPK介导组蛋白乙酰化如何调节人类AML，通过 生成急性髓系白血病患者来源的异种移植模型。综上所述，这项提议将在 代谢和表观遗传学，更具体地说是乙酰辅酶A代谢、AMPK和组蛋白之间的联系 乙酰化。我们假设，这些相互作用对于招募转录调控因子到Key是必不可少的 白血病基因。在下一个资金周期中，我们预计将公布新的见解，让我们了解如何 代谢调节剂可以作为靶点，使AML对表观遗传药物敏感，为开发新型药物铺平道路 组合疗法。

AML is the most common acute leukemia in adults, and it appears increasingly with age. Despite overall improvement in the treatment of leukemia, AML still carries a devastating prognosis for elderly patients (less than 10% of patients survive for 5 years). Thus, new therapies for AML are necessary. AMPK is a metabolic regulator that promotes catabolism and inhibits anabolism, thereby maintaining metabolic homeostasis upon metabolic stress. Using mouse models and AMPK inhibitors, we demonstrated that AMPK inhibition renders AML sensitive to metabolic stress induced by dietary restriction (Saito et al. Cell Stem Cell. 2015). During this study, we noticed that AMPK deletion reduces acetyl-coA and histone acetylation in AML (Fig. 2), concomitant with decreased expression of critical leukemia-promoting genes such as Myc. Importantly, chromatin immunoprecipitation and sequencing (ChIP-seq) revealed that AMPK deletion reduces the occupancy of acetylated histones, all of which marks active genes and recruits transcriptional regulators. We thus hypothesized that AMPK links metabolism to epigenetics in AML by maintaining histone acetylation. In aim 1 we will determine whether the occupancy of transcriptional regulators in AML is regulated by AMPK. In aim 2, we will determine how metabolites and the metabolic enzymes that produces acetyl-coA regulate histone acetylation. In aim 3, we will determine how AMPK-mediated histone acetylation regulates human AML, by generating patient-derived xenograft models of AML. Taken together, this proposal will establish the link between metabolism and epigenetics, more specifically the links between acetyl-CoA metabolism, AMPK, and histone acetylation. We hypothesize that these interactions are essential to recruit transcriptional regulators to key leukemogenic genes. In the next funding cycle, we anticipate to unveil new insights that will inform us on how metabolic regulators could be targeted to sensitize AML to epigenetic drugs, paving the way to novel combinatorial therapies.