The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia.
The Glycolytic Gatekeeper PDK1 defines different metabolic states between genetically distinct subtypes of human acute myeloid leukemia.
复制标题
DOI：
10.1038/s41467-022-28737-3
复制
发表时间：
2022-03-01
影响因子：
16.6
通讯作者：
Schuringa JJ
中科院分区：
文献类型：
--
作者：
Erdem A;Marin S;Pereira-Martins DA;Cortés R;Cunningham A;Pruis MG;de Boer B;van den Heuvel FAJ;Geugien M;Wierenga ATJ;Brouwers-Vos AZ;Rego EM;Huls G;Cascante M;Schuringa JJ
急性髓性白血病由于个体患者之间和内部的强烈遗传异质性，仍然难以治疗。在这里，我们发现丙酮酸脱氢酶激酶1 （PDK1）在急性髓性白血病（AML）中作为不同代谢状态的可靶向决定因素。PDK1low AMLs是oxphos驱动的，富含白血病粒细胞单核细胞祖细胞（L-GMP）特征，并且与FLT3-ITD和NPM1cyt突变有关。然而，PDK1high AMLs是OXPHOSlow， FLT3和NPM1的野生型，并且丰富了干性特征。个体患者体内不同基因亚克隆之间的代谢状态甚至可能不同。PDK1活性的丧失使糖酵解细胞进入与ROS水平升高相关的OXPHOS状态，导致白血病细胞凋亡增强，但在健康的干细胞/祖细胞中没有这种情况。这与人源化异种移植小鼠模型体外和体内对谷氨酰胺摄取的依赖性增强和增殖减少相一致。我们表明，人类白血病表现出独特的代谢状态和适应机制，可以作为治疗的目标。急性髓性白血病（AML）是一种遗传上非常异质性的疾病。在这里，Erdem等人揭示了AML代谢景观的异质性，并确定丙酮酸脱氢酶激酶1 （PDK1）是AML不同亚型中不同代谢状态的可靶向决定因素。
Acute myeloid leukemia remains difficult to treat due to strong genetic heterogeneity between and within individual patients. Here, we show that Pyruvate dehydrogenase kinase 1 (PDK1) acts as a targetable determinant of different metabolic states in acute myeloid leukemia (AML). PDK1low AMLs are OXPHOS-driven, are enriched for leukemic granulocyte-monocyte progenitor (L-GMP) signatures, and are associated with FLT3-ITD and NPM1cyt mutations. PDK1high AMLs however are OXPHOSlow, wild type for FLT3 and NPM1, and are enriched for stemness signatures. Metabolic states can even differ between genetically distinct subclones within individual patients. Loss of PDK1 activity releases glycolytic cells into an OXPHOS state associated with increased ROS levels resulting in enhanced apoptosis in leukemic but not in healthy stem/progenitor cells. This coincides with an enhanced dependency on glutamine uptake and reduced proliferation in vitro and in vivo in humanized xenograft mouse models. We show that human leukemias display distinct metabolic states and adaptation mechanisms that can serve as targets for treatment. Acute myeloid leukemia (AML) is genetically a very heterogeneous disease. Here, Erdem et al. uncover heterogeneity in the metabolic landscape of AML and identify Pyruvate dehydrogenase kinase 1 (PDK1) as a targetable determinant of different metabolic states in distinct subtypes of AML.
登录
查看更多内容
影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
2.6
作者：
Gregory MA;Nemkov T;Reisz JA;Zaberezhnyy V;Hansen KC;D'Alessandro A;DeGregori J
通讯作者：
DeGregori J
影响因子：
14.9
作者：
Gene Ontology Consortium
通讯作者：
Gene Ontology Consortium
影响因子：
20.3
作者：
Chen, Wen-Lian;Wang, Jing-Han;Jia, Wei
通讯作者：
Jia, Wei
DOI：
10.1126/science.aaf5530
发表时间：
2016-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Ito K;Turcotte R;Cui J;Zimmerman SE;Pinho S;Mizoguchi T;Arai F;Runnels JM;Alt C;Teruya-Feldstein J;Mar JC;Singh R;Suda T;Lin CP;Frenette PS;Ito K
通讯作者：
Ito K