Very long chain fatty acid metabolism is required in acute myeloid leukemia
Very long chain fatty acid metabolism is required in acute myeloid leukemia
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DOI：
10.1182/blood.2020008551
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发表时间：
2021-06-24
期刊：
影响因子：
20.3
通讯作者：
Spagnuolo, Paul A.
中科院分区：
文献类型：
--
作者：
Tcheng, Matthew;Roma, Alessia;Spagnuolo, Paul A.
急性髓性白血病（AML）细胞具有非典型代谢表型，其特征在于线粒体质量增加，以及更依赖氧化磷酸化和脂肪酸氧化（FAO）生存。为了利用这种改变的代谢，我们评估了公开可用的数据库，以确定FAO酶过表达。极长链酰基辅酶A脱氢酶（VLCAD; ACADVL）被发现过表达并且对白血病细胞线粒体代谢至关重要。VLCAD的遗传衰减或药理学抑制阻碍了线粒体呼吸和FAO对三羧酸循环的贡献，导致活力、增殖、克隆形成生长和AML细胞植入降低。在VLCAD抑制FAO引发丙酮酸脱氢酶活性的增加，这不足以增加糖酵解，但导致三磷酸腺苷耗尽和AML细胞死亡，对正常造血细胞没有影响。总之，这些结果证明了VLCAD在AML细胞生物学中的重要性，并强调了这种毁灭性疾病的新代谢脆弱性。
Acute myeloid leukemia (AML) cells have an atypical metabolic phenotype characterized by increased mitochondrial mass, as well as a greater reliance on oxidative phosphorylation and fatty acid oxidation (FAO) for survival. To exploit this altered metabolism, we assessed publicly available databases to identify FAO enzyme overexpression. Very long chain acyl-CoA dehydrogenase (VLCAD; ACADVL) was found to be overexpressed and critical to leukemia cell mitochondrial metabolism. Genetic attenuation or pharmacological inhibition of VLCAD hindered mitochondrial respiration and FAO contribution to the tricarboxylic acid cycle, resulting in decreased viability, proliferation, clonogenic growth, and AML cell engraftment. Suppression of FAO at VLCAD triggered an increase in pyruvate dehydrogenase activity that was insufficient to increase glycolysis but resulted in adenosine triphosphate depletion and AML cell death, with no effect on normal hematopoietic cells. Together, these results demonstrate the importance of VLCAD in AML cell biology and highlight a novel metabolic vulnerability for this devastating disease.