Metabolic Regulation in Leukemia-Initatiating Cells

白血病起始细胞的代谢调节

• 批准号: 9017971
• 负责人: Daisuke Nakada
• 金额: $ 46.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9017971
• 关键词: Acute Myelocytic Leukemia; Adipose tissue; Affect; Anorexia; Antioxidants; Attenuated; CRISPR/Cas technology; Cachexia; Cancer Intervention; Cancer Patient; Carbon; Cell physiology; Cells; Clinical; Complex; Dependence; Development; Diet; Enzymes; Glucose; Glucose Transporter; Goals; Health; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; In Vitro; Intervention; Lead; Leukemic Cell; MLL-AF9; Malignant Neoplasms; Malnutrition; Metabolic; Metabolic stress; Molecular; Monitor; Mus; Nature; Normal Cell; Organ; Oxidative Stress; Pathway interactions; Patients; Physiological; Reactive Oxygen Species; Reducing Agents; Regimen; Regulation; Reporting; Resistance; Role; Skeletal Muscle; Starvation; Stress; Syndrome; System; Testing; Therapeutic; biological adaptation to stress; cancer cachexia; cancer cell; deprivation; dietary control; dietary manipulation; dietary restriction; glucose metabolism; glucose uptake; improved; in vivo; in vivo Model; inhibitor/antagonist; killings; leukemia; leukemogenesis; mortality; novel; research study; small molecule inhibitor; targeted treatment; upstream kinase; wasting

 DESCRIPTION (provided by applicant): Cancer cachexia is a complex multi-organ syndrome associated with anorexia and severe wasting of adipose tissue and skeletal muscle, contributing to the mortality of many patients. Even under this metabolic mayhem, cancer cells are somewhat protected from starvation and continue to expand. This raises a fundamental question of how cancer cells are protected from metabolic stress during cachexia. Understanding this cancer protective mechanism may lead to novel intervention to kill cancer cells under cachectic conditions, thereby improving patients' health. Particularly, development of cancer interventions rendering cancer cells sensitive to malnutrition observed in cachectic patients should be a valuable therapeutic option. We have evidence to suggest that AMPK, which senses energy stress and promotes metabolic homeostasis, may constitute this cancer protective mechanism. In preliminary results, we found that AMPK deletion from MLL-AF9 induced acute myelogenous leukemia (AML) significantly delayed the onset of AML, depleted leukemia-initiating cells (LICs), and disrupted metabolic homeostasis of AML cells. In contrast, deleting AMPK did not affect normal hematopoiesis, demonstrating that leukemic cells are more dependent on AMPK than normal hematopoietic cells. We further found that AMPK-deficient AML LICs are particularly sensitive to glucose deprivation in vitro. Strikingly, the delayed onset of leukemogenesis by AMPK-deficient AML was further delayed by placing the recipient mice on dietary restriction (DR), indicating that physiological metabolic stress in vivo renders leukemia particularly dependent on AMPK. We thus hypothesized that AMPK is required for LICs to resist metabolic stress, and that combining AMPK inhibition with dietary manipulation will suppress AML by disabling the metabolic stress response of AML. Our long-term goal is to understand how leukemia-initiating cells utilize metabolic regulators to survive malnourished conditions often found in cancer patients. In aim 1, we will determine how AMPK promotes the metabolic homeostasis of AML cells, by performing metabolic flux analysis and quantifying various metabolites in AML cells. In aim 2, we will determine how AMPK inhibition and dietary manipulation synergize to suppress leukemogenesis. In aim 3, we will test our hypothesis that Glut1 is a critical regulator of leukemogenesis controlled by AMPK, by deleting and/or inhibiting Glut1. We will also delete other candidate metabolic enzymes that regulate glucose metabolism and examine their function in leukemogenesis and conferring metabolic stress resistance to AML cells. Upon completion of this proposal, we will have deep understanding of the role of AMPK pathway in maintaining leukemia-initiating cells under metabolic stress. Since AMPK is not required for normal hematopoiesis, AMPK inhibition combined with dietary control shown in our study may offer a novel anti-leukemia therapy that targets leukemia without impairing normal HSCs and hematopoiesis.

 描述(申请人提供)：癌症恶病质是一种复杂的多器官综合征，与厌食和严重的脂肪组织和骨骼肌消耗有关，导致许多患者死亡。即使在这种代谢混乱的情况下，癌细胞也在某种程度上免受饥饿并继续扩张。这提出了一个根本性的问题，即在恶病质期间，癌细胞如何免受代谢压力的影响。了解这种癌症保护机制可能会导致新的干预措施，在恶病质条件下杀死癌细胞，从而改善患者的健康。特别是，开发癌症干预措施，使癌细胞对恶病质患者观察到的营养不良敏感，应该是一个有价值的治疗选择。我们有证据表明，AMPK可能构成了这种癌症保护机制，AMPK可以感知能量压力并促进代谢稳态。在初步结果中，我们发现从MLL-AF9诱导的急性髓系白血病(AML)中AMPK的缺失显著延迟了AML的发病，耗尽了白血病启动细胞(LICs)，并破坏了AML细胞的代谢稳态。相比之下，删除AMPK并不影响正常的造血，这表明白血病细胞比正常的造血细胞更依赖AMPK。我们进一步发现AMPK缺陷的AML LIC对体外缺糖特别敏感。值得注意的是，AMPK缺乏的AML通过限制饮食(DR)进一步推迟了白血病的延迟发生，这表明体内的生理性代谢应激使白血病对AMPK特别依赖。因此，我们假设AMPK是LIC抵抗代谢应激所必需的，并且AMPK抑制和饮食控制相结合将通过禁用AML的代谢应激反应来抑制AML。我们的长期目标是了解启动白血病的细胞如何利用代谢调节器在癌症患者常见的营养不良条件下生存下来。在目标1中，我们将通过进行代谢流量分析和量化AML细胞中的各种代谢物来确定AMPK如何促进AML细胞的代谢动态平衡。在目标2中，我们将确定AMPK抑制和饮食操作如何协同抑制白血病的发生。在目标3中，我们将通过删除和/或抑制Glut1来验证我们的假设，即Glut1是由AMPK控制的白血病发生的关键调节因子。我们还将删除其他调节葡萄糖代谢的候选代谢酶，并检测它们在白血病发生和赋予AML细胞代谢应激抵抗中的功能。这项研究完成后，我们将对AMPK通路在维持代谢应激状态下的白血病启动细胞中的作用有更深入的了解。由于AMPK不是正常造血所必需的，我们的研究表明，AMPK抑制与饮食控制相结合可能提供一种新的抗白血病疗法，在不损害正常HSCs和造血的情况下针对白血病。