Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy.
Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy.
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DOI：
10.1016/j.cmet.2020.09.001
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发表时间：
2020-11-03
期刊：
影响因子：
29
通讯作者：
Méndez-Ferrer S
中科院分区：
文献类型：
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作者：
Forte D;García-Fernández M;Sánchez-Aguilera A;Stavropoulou V;Fielding C;Martín-Pérez D;López JA;Costa ASH;Tronci L;Nikitopoulou E;Barber M;Gallipoli P;Marando L;Fernández de Castillejo CL;Tzankov A;Dietmann S;Cavo M;Catani L;Curti A;Vázquez J;Frezza C;Huntly BJ;Schwaller J;Méndez-Ferrer S
像正常的造血干细胞一样，白血病干细胞依赖于它们的骨髓微环境存活，但其潜在的机制在很大程度上仍然未知。我们研究了巢蛋白+骨髓间充质干细胞（BMSCs）在mml - af9驱动的急性髓系白血病（AML）发展和体内化疗耐药中的作用。与大块基质不同，巢蛋白+骨髓间充质干细胞的数量在AML中不会减少，但它们的功能改变以支持AML细胞，牺牲非突变的造血干细胞（hsc）。巢蛋白+细胞耗损延缓原发性AML小鼠的白血病发生，选择性地减少嵌合小鼠的AML细胞，而不是正常细胞。Nestin+ BMSCs通过增加氧化磷酸化、三羧酸（TCA）循环活性和谷胱甘肽（GSH）介导的抗氧化防御来支持AML的生存和化疗复发。因此，AML细胞利用骨髓间充质干细胞的能量来源和抗氧化防御机制来生存化疗。Nestin+骨髓基质细胞支持白血病发生和化疗耐药BMSCs支持LSCs的代谢需求BMSCs为LSCs提供必要的抗氧化防御，抵抗化疗GSH和GSH过氧化物酶，这是BMSCs衍生的抗氧化AML保护的基础Forte等人发现，在急性髓性白血病体内模型中，Nestin+骨髓基质细胞直接促进白血病发生和化疗耐药。巢蛋白+骨髓间充质干细胞通过增加生物能量能力的双重机制支持白血病干细胞，通过OXPHOS和TCA和谷胱甘肽依赖的抗氧化防御。
Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy. Nestin+ BMSCs support leukemogenesis and chemoresistance BMSCs support metabolic requirements of LSCs BMSCs provide LSCs with essential antioxidant defense from chemotherapy GSH and GSH peroxidases underlie BMSC-derived antioxidant AML protection Forte et al. reveal that nestin+ bone marrow stromal cells directly contribute to leukemogenesis and chemotherapy resistance in an in vivo model of acute myeloid leukemia. Nestin+ BMSCs support leukemic stem cells through a dual mechanism of increased bioenergetic capacity through OXPHOS and TCA and glutathione-dependent antioxidant defense.
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影响因子：
--
作者：
Boutter J;Huang Y;Marovca B;Vonderheit A;Grotzer MA;Eckert C;Cario G;Wollscheid B;Horvath P;Bornhauser BC;Bourquin JP
通讯作者：
Bourquin JP
影响因子：
64.5
作者：
Baryawno, Ninib;Przybylski, Dariusz;Scadden, David T.
通讯作者：
Scadden, David T.
影响因子：
3.7
作者：
Cardona M;López JA;Serafín A;Rongvaux A;Inserte J;García-Dorado D;Flavell R;Llovera M;Cañas X;Vázquez J;Sanchis D
通讯作者：
Sanchis D
影响因子：
20.3
作者：
Ben-Batalla, Isabel;Schultze, Alexander;Loges, Sonja
通讯作者：
Loges, Sonja
影响因子：
4.4
作者：
Bonzon-Kulichenko, Elena;Garcia-Marques, Fernando;Vazquez, Jesus
通讯作者：
Vazquez, Jesus