AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells.
AMPK/FIS1-Mediated Mitophagy Is Required for Self-Renewal of Human AML Stem Cells.
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DOI：
10.1016/j.stem.2018.05.021
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发表时间：
2018-07-05
期刊：
影响因子：
23.9
通讯作者：
Jordan CT
中科院分区：
文献类型：
--
作者：
Pei S;Minhajuddin M;Adane B;Khan N;Stevens BM;Mack SC;Lai S;Rich JN;Inguva A;Shannon KM;Kim H;Tan AC;Myers JR;Ashton JM;Neff T;Pollyea DA;Smith CA;Jordan CT
白血病干细胞(LSCs)被认为是急性髓系白血病(AML)发生和化疗后复发的原因。由于其独特的生物学特性，开发有效的方法来根除LSCs一直是一个巨大的挑战。在目前的研究中，我们证明了线粒体动力学调节因子FIS1的内在过度表达介导了对原始AML细胞至关重要的有丝分裂活性。FIS1的缺失减弱了吞噬有丝分裂，导致GSK3失活，髓系分化，细胞周期停滞，LSC自我更新能力的严重丧失。此外，我们报告了中枢代谢应激调节因子AMPK在LSC人群中也被固有地激活，并且位于FIS1的上游。AMPK信号通路的抑制重述了FIS1缺失的生物学效应。这些数据提出了一种模型，在该模型中，LSCs共同选择AMPK/FIS1介导的有丝分裂作为维持干细胞特性的一种手段，否则干细胞特性可能会受到致癌转化诱导的压力的影响。人急性髓系白血病干细胞(LSCs)依赖于FIS1介导的有丝分裂吞噬功能进行自我更新和存活。AMPK在人类LSCs中具有结构性活性，位于FIS1的上游，具有刺激有丝分裂的作用。AMPK信号或FIS1活性的中断会导致LSCs的根除。
Leukemia stem cells (LSCs) are thought to drive the genesis of acute myeloid leukemia (AML) as well as relapse following chemotherapy. Due to their unique biology, developing effective methods to eradicate LSCs has been a significant challenge. In the present study, we demonstrate that intrinsic over-expression of the mitochondrial dynamics regulator FIS1 mediates mitophagy activity that is essential for primitive AML cells. Depletion of FIS1 attenuates mitophagy and leads to inactivation of GSK3, myeloid differentiation, cell cycle arrest and a profound loss of LSC self-renewal potential. Further, we report the central metabolic stress regulator AMPK is also intrinsically activated in LSC populations and is upstream of FIS1. Inhibition of AMPK signaling recapitulates the biological effect of FIS1 loss. These data suggest a model in which LSCs co-opt AMPK/FIS1-mediated mitophagy as a means to maintain stem cell properties that may be otherwise compromised by the stresses induced by oncogenic transformation. Human acute myeloid leukemia stem cells (LSCs) depend on FIS1-mediated mitophagy for self-renewal and survival. AMPK is constitutively active in human LSCs, is upstream of FIS1, and acts to stimulate mitophagy. Disruption of AMPK signaling or FIS1 activity results in eradication of LSCs.
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
46.9
作者：
Doench JG;Fusi N;Sullender M;Hegde M;Vaimberg EW;Donovan KF;Smith I;Tothova Z;Wilen C;Orchard R;Virgin HW;Listgarten J;Root DE
通讯作者：
Root DE
影响因子：
120.7
作者：
Gentles, Andrew J.;Plevritis, Sylvia K.;Majeti, Ravindra;Alizadeh, Ash A.
通讯作者：
Alizadeh, Ash A.
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
20.3
作者：
Ho, Tzu-Chieh;LaMere, Mark;Becker, Michael W.
通讯作者：
Becker, Michael W.