全基因组CRISPR/Cas9文库筛选发现OGDH是骨髓增生异常性肿瘤疾病进展和对地西他滨耐药性的调节因子,其作用是对谷氨酰胺代谢进行重编程

IF 12.8 1区 医学 Q1 HEMATOLOGY Leukemia Pub Date : 2024-09-03 DOI:10.1038/s41375-024-02377-6
Xiaoyan Xu, Jiaqian Qi, Hong Wang, Ziyan Zhang, Tingting Pan, Xueqian Li, Jingyi Yang, Haohao Han, Mengting Guo, Meng Zhou, Chengsen Cai, Yaqiong Tang, Qixiu Hou, Suning Chen, Depei Wu, Yue Han
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引用次数: 0

摘要

骨髓增生异常肿瘤(MDS)是造血干细胞的克隆性疾病,以无效造血、全血细胞减少和发育不良为特征,通常会发展为急性髓性白血病(AML)[1]。地西他滨(DAC)是一种低甲基化药物(HMAs),在 MDS 的治疗中起着至关重要的作用 [2]。然而,HMAs 的完全缓解率仍然很低,仅为 15-20%,而且近一半的患者最终会在治疗过程中产生耐药性[3, 4]。MDS对地西他滨耐药的分子机制仍未完全明了[5]。随着对肿瘤发病机制认识的不断深入,代谢重编程,尤其是谷氨酰胺还原羧化的增强或氧化磷酸化的破坏,也被报道与血液恶性肿瘤的耐药性密切相关[6, 7]。在此,研究人员采用全基因组CRISPR/Cas9文库筛选和全外显子组测序(WES)相结合的方法,以鉴定涉及地西他滨敏感性的候选基因。OGDH编码三羧酸(TCA)循环中的一种关键酶,被确定为MDS对地西他滨耐药的调控因子。我们在体外和体内探讨了 OGDH 在调节谷氨酰胺代谢中的生物学功能。总之,我们首次报道了 OGDH 的低表达会增强 MDS 中谷氨酰胺的还原代谢。这些结果突显了 OGDH 在地西他滨耐药性中的重要作用,并为 MDS 的潜在治疗策略(包括靶向谷氨酰胺酶 (GLS))提供了启示。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Genome-wide CRISPR/Cas9 library screening identified OGDH as a regulator of disease progress and resistance to decitabine in myelodysplastic neoplasm by reprogramming glutamine metabolism
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来源期刊
Leukemia
Leukemia 医学-血液学
CiteScore
18.10
自引率
3.50%
发文量
270
审稿时长
3-6 weeks
期刊介绍: Title: Leukemia Journal Overview: Publishes high-quality, peer-reviewed research Covers all aspects of research and treatment of leukemia and allied diseases Includes studies of normal hemopoiesis due to comparative relevance Topics of Interest: Oncogenes Growth factors Stem cells Leukemia genomics Cell cycle Signal transduction Molecular targets for therapy And more Content Types: Original research articles Reviews Letters Correspondence Comments elaborating on significant advances and covering topical issues
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