NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts
NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts
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DOI：
10.1182/blood-2017-03-772939
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发表时间：
2017-10-05
期刊：
影响因子：
20.3
通讯作者：
Rushworth, Stuart A.
中科院分区：
文献类型：
--
作者：
Marlein, Christopher R.;Zaitseva, Lyubov;Rushworth, Stuart A.
对癌症和其微环境之间代谢串扰的理解的改进有望导致新的治疗方法。与非恶性CD 34（+）造血祖细胞相比，急性髓性白血病（AML）细胞的线粒体增多。此外，与瓦尔堡假说相反，AML依赖于氧化磷酸化产生三磷酸腺苷。在这里，我们报告说，在人类AML，NOX 2产生超氧化物，刺激骨髓基质细胞（BMSC）AML通过AML衍生的隧道纳米管的线粒体转移。此外，抑制NOX 2能够阻止线粒体转移，增加AML凋亡，并改善NSG AML小鼠的存活率。尽管线粒体从BMSC转移到非恶性CD 34（+）细胞是对氧化应激的反应，但抑制NOX 2对非恶性CD 34（+）细胞的存活没有可检测的影响。总之，我们确定了肿瘤特异性依赖于NOX 2驱动的线粒体转移作为AML的一种新的治疗策略。
Improvements in the understanding of the metabolic cross-talk between cancer and itsmicroenvironment are expected to lead to novel therapeutic approaches. Acute myeloid leukemia (AML) cells have increased mitochondria compared with nonmalignant CD34(+) hematopoietic progenitor cells. Furthermore, contrary to the Warburg hypothesis, AML relies on oxidative phosphorylation to generate adenosine triphosphate. Here we report that in human AML, NOX2generates superoxide, which stimulates bonemarrow stromal cells (BMSC) toAMLblast transfer of mitochondria through AML-derived tunneling nanotubes. Moreover, inhibition of NOX2 was able to prevent mitochondrial transfer, increase AML apoptosis, and improve NSG AMLmouse survival. Although mitochondrial transfer fromBMSC to nonmalignant CD34(+) cells occurs in response tooxidativestress, NOX2inhibitionhadnodetectable effectonnonmalignantCD34(+) cellsurvival. Taken together, we identify tumor-specific dependence on NOX2-driven mitochondrial transfer as a novel therapeutic strategy in AML.