Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells.
Inhibition of Amino Acid Metabolism Selectively Targets Human Leukemia Stem Cells.
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DOI：
10.1016/j.ccell.2018.10.005
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发表时间：
2018-11-12
期刊：
影响因子：
50.3
通讯作者：
Jordan CT
中科院分区：
文献类型：
--
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
在这项研究中，我们询问了人类急性髓性白血病（AML）干细胞的代谢组，以阐明与治疗干预相关的特性。我们证明，氨基酸摄取，稳态水平，和catalysts都在白血病干细胞（LSC）人口的升高。此外，从新生AML患者分离的LSC独特地依赖于氨基酸代谢以实现氧化磷酸化和存活。氨基酸代谢的药理学抑制减少氧化磷酸化并诱导细胞死亡。相比之下，从复发性AML患者获得的LSC不依赖于氨基酸代谢，因为它们能够通过增加的脂肪酸代谢进行补偿。这些发现表明，LSC的临床相关根除可以通过靶向LSC代谢脆弱性的药物来实现。通过研究人类急性髓性白血病的代谢特性，Jones等人揭示了白血病干细胞（LSC）中氨基酸代谢的增加，这些细胞依赖氨基酸进行氧化磷酸化和存活。维奈托克与阿扎胞苷通过降低氨基酸摄取诱导LSC毒性。
In this study we interrogated the metabolome of human acute myeloid leukemia (AML) stem cells to elucidate properties relevant to therapeutic intervention. We demonstrate that amino acid uptake, steady-state levels, and catabolism are all elevated in the leukemia stem cell (LSC) population. Furthermore, LSCs isolated from de novo AML patients are uniquely reliant on amino acid metabolism for oxidative phosphorylation and survival. Pharmacological inhibition of amino acid metabolism reduces oxidative phosphorylation and induces cell death. In contrast, LSCs obtained from relapsed AML patients are not reliant on amino acid metabolism due to their ability to compensate through increased fatty acid metabolism. These findings indicate that clinically relevant eradication of LSCs can be achieved with drugs that target LSC metabolic vulnerabilities. By interrogating metabolic properties of human acute myeloid leukemia, Jones et al. reveal increased amino acid metabolism in leukemia stem cells (LSCs), which rely on amino acids for oxidative phosphorylation and survival. Venetoclax with azacitidine induces LSC toxicity by decreasing amino acid uptake.
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