当前位置: X-MOL 学术Nat. Med. › 论文详情
Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)
Venetoclax with azacitidine disrupts energy metabolism and targets leukemia stem cells in patients with acute myeloid leukemia.
Nature Medicine ( IF 58.7 ) Pub Date : 2018-11-12 , DOI: 10.1038/s41591-018-0233-1
Daniel A Pollyea 1 , Brett M Stevens 1 , Courtney L Jones 1 , Amanda Winters 2 , Shanshan Pei 1 , Mohammad Minhajuddin 1 , Angelo D'Alessandro 3 , Rachel Culp-Hill 3 , Kent A Riemondy 4 , Austin E Gillen 4 , Jay R Hesselberth 3, 4 , Diana Abbott 5 , Derek Schatz 1 , Jonathan A Gutman 1 , Enkhtsetseg Purev 1 , Clayton Smith 1 , Craig T Jordan 1
Affiliation  

Acute myeloid leukemia (AML) is the most common acute leukemia in adults. Leukemia stem cells (LSCs) drive the initiation and perpetuation of AML, are quantifiably associated with worse clinical outcomes, and often persist after conventional chemotherapy resulting in relapse1-5. In this report, we show that treatment of older patients with AML with the B cell lymphoma 2 (BCL-2) inhibitor venetoclax in combination with azacitidine results in deep and durable remissions and is superior to conventional treatments. We hypothesized that these promising clinical results were due to targeting LSCs. Analysis of LSCs from patients undergoing treatment with venetoclax + azacitidine showed disruption of the tricarboxylic acid (TCA) cycle manifested by decreased α-ketoglutarate and increased succinate levels, suggesting inhibition of electron transport chain complex II. In vitro modeling confirmed inhibition of complex II via reduced glutathionylation of succinate dehydrogenase. These metabolic perturbations suppress oxidative phosphorylation (OXPHOS), which efficiently and selectively targets LSCs. Our findings show for the first time that a therapeutic intervention can eradicate LSCs in patients with AML by disrupting the metabolic machinery driving energy metabolism, resulting in promising clinical activity in a patient population with historically poor outcomes.

中文翻译:

具有阿扎胞苷的Venetoclax会破坏能量代谢,并靶向急性髓细胞性白血病患者的白血病干细胞。

急性髓细胞性白血病(AML)是成人中最常见的急性白血病。白血病干细胞(LSC)驱动AML的发生和延续,在数量上与较差的临床结果相关,并且在常规化疗后通常持续存在,导致复发1-5。在本报告中,我们显示B细胞淋巴瘤2(BCL-2)抑制剂Venetoclax与阿扎胞苷联合治疗老年AML患者可产生深度和持久的缓解,且优于常规治疗。我们假设这些有希望的临床结果归因于靶向LSC。对接受venetoclax +阿扎胞苷治疗的患者的LSC的分析表明,三羧酸(TCA)周期受到破坏,表现为α-酮戊二酸减少和琥珀酸水平增加,提示抑制电子传输链复合物II。体外建模证实了通过减少琥珀酸脱氢酶的谷胱甘肽化对复合物II的抑制。这些新陈代谢扰动抑制了氧化磷酸化(OXPHOS),该氧化磷酸化可有效和选择性地靶向LSC。我们的发现首次表明,治疗干预可以通过破坏驱动能量代谢的代谢机制来根除AML患者的LSC,从而在历史上效果欠佳的患者人群中带来有希望的临床活动。
更新日期:2018-11-13
down
wechat
bug