ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling.
ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling.
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ABAT基因表达通过CXCR4/mTOR信号通路与骨髓增生异常综合征中低甲基化药物的敏感性相关。
DOI：
10.1038/s41420-022-01170-7
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发表时间：
2022-09-26
影响因子：
7
通讯作者：
Wang, Xiaoqin
中科院分区：
文献类型：
--
作者：
Zhao, Guangjie;Li, Shuang;Wang, Qian;Wu, Wanlin;Fu, Xuewei;Zhu, Chen;Wang, Wei;Wang, Xiaoqin
影响骨髓增生异常综合征（MDS）低甲基化药物（HMAs）敏感性的因素是复杂和多方面的。它们包括DNA甲基化、基因表达、突变等，然而，其潜在的机制仍然没有清楚地阐明。在本研究中，ABAT基因表达与HMAs敏感性相关。ABAT基因干扰可增加HL-60和THP-1细胞对HMAs的敏感性，而ABAT基因过表达则降低其敏感性。RNA测序分析表明，ABAT敲低激活干扰素I和干扰素-γ信号，同时抑制次级代谢合成和精氨酸代谢过程。基于气相色谱-质谱（GC-MS）的代谢分析也表明，ABAT基因敲除影响精氨酸，丙氨酸，天冬氨酸和谷氨酸的代谢，除了缬氨酸，亮氨酸和异亮氨酸的生物合成，和β-丙氨酸的代谢。ABAT基因表达下调可激活CXCR 4/mTOR信号通路，与HMAs敏感性相关。CXCR 4表达受mTOR活性调节，反之亦然。在体内，注射ABAT基因敲低细胞的小鼠在HMAs治疗后比对照小鼠活得更长。总之，本研究阐明了HMAs敏感性的新的调节机制，并提供了MDS的潜在治疗靶点。
The factors that affect hypomethylating agents (HMAs) sensitivity in myelodysplastic syndrome (MDS) are complex and multifaceted. They include DNA methylation, gene expression, mutation, etc. However, the underlying mechanisms are still not clearly illustrated. In the present work, ABAT gene expression was associated with HMAs sensitivity. It was found that ABAT gene interference increased the sensitivity of HL-60 and THP-1 cells to HMAs treatment, while ABAT overexpression decreased its sensitivity. RNA-sequencing analysis showed that ABAT knockdown activated both interferon I and interferon-gamma signaling while inhibiting the secondary metabolic synthesis and arginine metabolic process. Gas chromatography-mass spectrometry (GC-MS) based metabolic profiling also demonstrated that ABAT gene knockdown affected arginine, alanine, aspartate, and glutamate metabolism, in addition to the biosynthesis of valine, leucine, and isoleucine, and the metabolism of beta-alanine. The ABAT gene expression downregulation could activate the CXCR4/mTOR signaling pathway, which was related to HMAs sensitivity. CXCR4 expression was regulated by mTOR activity and vice versa. In vivo, mice injected with ABAT gene knockdown cells lived longer than control mice after HMAs treatment. Overall, this study elucidates the novel regulatory mechanisms of HMAs sensitivity and provides a potential therapeutic target in MDS.
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影响因子：
16.6
作者：
Villar VH;Nguyen TL;Delcroix V;Terés S;Bouchecareilh M;Salin B;Bodineau C;Vacher P;Priault M;Soubeyran P;Durán RV
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发表时间：
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影响因子：
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作者：
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影响因子：
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作者：
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影响因子：
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