ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways.
ChREBP promotes the differentiation of leukemia-initiating cells to inhibit leukemogenesis through the TXNIP/RUNX1 pathways.
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DOI：
10.18632/oncotarget.9520
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发表时间：
2016-06-21
期刊：
影响因子：
--
通讯作者：
Zheng J
中科院分区：
文献类型：
--
作者：
Zeng H;Gu H;Chen C;Li M;Xia F;Xie L;Liu X;Zhang F;Tong X;Wang J;Yu Z;Zheng J
靶向白血病起始细胞（LIC）是根除白血病并防止其复发的关键。最近的研究表明，代谢调节可能在维持 LIC 的干性中发挥关键作用，尽管详细机制尚不清楚。在此，我们提供了有趣的证据，表明葡萄糖反应性转录因子碳水化合物反应性元件结合蛋白（ChREBP）作为肿瘤抑制因子而不是癌基因，如之前所述，通过促进 LIC 的分化来抑制急性髓系白血病的发展。使用 MLL-AF9 诱导的小鼠白血病模型，我们证明 ChREBP 的缺失会导致 LIC 分化受阻，并显着降低 ChREBP 缺失的白血病小鼠的存活率。然而，ChREBP 并不是造血干细胞正常增殖能力所必需的。 ChREBP 通过直接抑制 RUNX1 或反式激活 TXNIP 下调 RUNX1 水平和 ROS 生成来促进白血病细胞分化。此外，人白血病THP1细胞中ChREBP的敲低导致PMA处理后增殖显着增强并分化减少。总的来说，我们揭示了 ChREBP 在白血病发生中的意想不到的作用，这可能为开发白血病治疗的新代谢策略提供有价值的线索。
Targeting leukemia-initiating cells (LICs) is the key to eradicating leukemia and preventing its relapse. Recent studies have indicated that metabolic regulation may play a critical role in the maintenance of stemness in LICs, although the detailed mechanisms are poorly understood. Herein, we provide intriguing evidence showing that a glucose-responsive transcription factor, carbohydrate responsive element binding protein (ChREBP), served as a tumor suppressor rather than an oncogene, as previously described, to inhibit the development of acute myeloid leukemia by promoting the differentiation of LICs. Using an MLL-AF9-induced murine leukemia model, we demonstrated that the deletion of ChREBP resulted in the blockage of the differentiation of LICs and significantly reduced survival in ChREBP-null leukemic mice. However, ChREBP was not required for the normal repopulation abilities of hematopoietic stem cells. ChREBP promoted leukemia cell differentiation through the direct inhibition of RUNX1 or the transactivation of TXNIP to downregulate the RUNX1 level and ROS generation. Moreover, knockdown of ChREBP in human leukemia THP1 cells led to markedly enhanced proliferation and decreased differentiation upon PMA treatment. Collectively, we unraveled an unexpected role of ChREBP in leukemogenesis, which may provide valuable clues for developing novel metabolic strategies for leukemia treatment.
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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.
DOI：
10.1084/jem.20100523
发表时间：
2010-04-12
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Abdel-Wahab O;Levine RL
通讯作者：
Levine RL
影响因子：
4.8
作者：
Ma, L;Tsatsos, NG;Towle, HC
通讯作者：
Towle, HC
影响因子：
5.3
作者：
Giannoni, E;Buricchi, F;Chiarugi, P
通讯作者：
Chiarugi, P
DOI：
10.1016/s0190-9622(97)70174-9
发表时间：
1997-10-01
影响因子：
13.8
作者：
Baer, SC;Casaubon, L;Younes, M
通讯作者：
Younes, M