Metabolic Regulation in Leukemia-Initatiating Cells

白血病起始细胞的代谢调节

基本信息

  • 批准号:
    9017971
  • 负责人:
  • 金额:
    $ 46.22万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

 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.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Daisuke Nakada其他文献

Daisuke Nakada的其他文献

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{{ truncateString('Daisuke Nakada', 18)}}的其他基金

Project 2: The role of the DNA damage response in clonal competition following genotoxic stress
项目 2:DNA 损伤反应在基因毒性应激后克隆竞争中的作用
  • 批准号:
    10332336
  • 财政年份:
    2022
  • 资助金额:
    $ 46.22万
  • 项目类别:
Mechanisms that regulate erythroid differentiation of hematopoietic stem cells
造血干细胞红系分化的调节机制
  • 批准号:
    10509652
  • 财政年份:
    2022
  • 资助金额:
    $ 46.22万
  • 项目类别:
Project 2: The role of the DNA damage response in clonal competition following genotoxic stress
项目 2:DNA 损伤反应在基因毒性应激后克隆竞争中的作用
  • 批准号:
    10606554
  • 财政年份:
    2022
  • 资助金额:
    $ 46.22万
  • 项目类别:
Mechanisms that regulate erythroid differentiation of hematopoietic stem cells
造血干细胞红系分化的调节机制
  • 批准号:
    10647781
  • 财政年份:
    2022
  • 资助金额:
    $ 46.22万
  • 项目类别:
THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
  • 批准号:
    10659193
  • 财政年份:
    2021
  • 资助金额:
    $ 46.22万
  • 项目类别:
THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
  • 批准号:
    10434125
  • 财政年份:
    2021
  • 资助金额:
    $ 46.22万
  • 项目类别:
THE ROLE OF SELENOPROTEIN SYNTHESIS PATHWAY IN ACUTE MYELOID LEUKEMIA
硒蛋白合成途径在急性髓系白血病中的作用
  • 批准号:
    10296885
  • 财政年份:
    2021
  • 资助金额:
    $ 46.22万
  • 项目类别:
Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging
间充质基质细胞调节造血干细胞衰老
  • 批准号:
    9404451
  • 财政年份:
    2016
  • 资助金额:
    $ 46.22万
  • 项目类别:
Mesenchymal Stromal Cells Regulate Hematopoietic Stem Cell Aging
间充质基质细胞调节造血干细胞衰老
  • 批准号:
    9189715
  • 财政年份:
    2016
  • 资助金额:
    $ 46.22万
  • 项目类别:
Metabolic Regulation in Leukemia-Initatiating Cells
白血病起始细胞的代谢调节
  • 批准号:
    9245651
  • 财政年份:
    2015
  • 资助金额:
    $ 46.22万
  • 项目类别:

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