{"title":"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","authors":"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","doi":"10.1038/s41375-024-02377-6","DOIUrl":null,"url":null,"abstract":"<p>Myelodysplastic neoplasms (MDS) are clonal disorders of hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenia, and dysplasia, which often progress to acute myeloid leukemia (AML) [1]. Decitabine (DAC), a hypomethylating agents (HMAs), plays a crucial role in the treatment of MDS [2]. However, the complete remission rate with HMAs remains low at 15–20%, and nearly half of the patients ultimately develop resistance during therapy [3, 4]. The molecular mechanisms underlying resistance to decitabine in MDS are still not fully understood [5]. With an increasing understanding of tumor pathogenesis, metabolic reprogramming, especially enhanced reductive carboxylation of glutamine or disrupted oxidative phosphorylation, is also reported to be closely associated with drug resistance in hematological malignancies [6, 7].</p><p>Herein, a combination of genome-wide CRISPR/Cas9 library screening and whole exome sequencing (WES) was employed to identify candidate genes involved in decitabine sensitivity. <i>OGDH</i>, which encodes a key enzyme in the tricarboxylic acid (TCA) cycle, was identified as a regulator of resistance to decitabine in MDS. The biological functions of <i>OGDH</i> in regulating glutamine metabolism were explored both in vitro and in vivo. Overall, we first reported that low expression of <i>OGDH</i> enhances reductive glutamine metabolism in MDS. The results highlight the important role of <i>OGDH</i> in resistance to decitabine and provide insights into potential therapeutic strategies for MDS, including targeting glutaminase (GLS).</p>","PeriodicalId":18109,"journal":{"name":"Leukemia","volume":null,"pages":null},"PeriodicalIF":12.8000,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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\",\"authors\":\"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\",\"doi\":\"10.1038/s41375-024-02377-6\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>Myelodysplastic neoplasms (MDS) are clonal disorders of hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenia, and dysplasia, which often progress to acute myeloid leukemia (AML) [1]. Decitabine (DAC), a hypomethylating agents (HMAs), plays a crucial role in the treatment of MDS [2]. However, the complete remission rate with HMAs remains low at 15–20%, and nearly half of the patients ultimately develop resistance during therapy [3, 4]. The molecular mechanisms underlying resistance to decitabine in MDS are still not fully understood [5]. With an increasing understanding of tumor pathogenesis, metabolic reprogramming, especially enhanced reductive carboxylation of glutamine or disrupted oxidative phosphorylation, is also reported to be closely associated with drug resistance in hematological malignancies [6, 7].</p><p>Herein, a combination of genome-wide CRISPR/Cas9 library screening and whole exome sequencing (WES) was employed to identify candidate genes involved in decitabine sensitivity. <i>OGDH</i>, which encodes a key enzyme in the tricarboxylic acid (TCA) cycle, was identified as a regulator of resistance to decitabine in MDS. The biological functions of <i>OGDH</i> in regulating glutamine metabolism were explored both in vitro and in vivo. Overall, we first reported that low expression of <i>OGDH</i> enhances reductive glutamine metabolism in MDS. The results highlight the important role of <i>OGDH</i> in resistance to decitabine and provide insights into potential therapeutic strategies for MDS, including targeting glutaminase (GLS).</p>\",\"PeriodicalId\":18109,\"journal\":{\"name\":\"Leukemia\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":12.8000,\"publicationDate\":\"2024-09-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Leukemia\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41375-024-02377-6\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"HEMATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Leukemia","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41375-024-02377-6","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}
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
Myelodysplastic neoplasms (MDS) are clonal disorders of hematopoietic stem cells, characterized by ineffective hematopoiesis, cytopenia, and dysplasia, which often progress to acute myeloid leukemia (AML) [1]. Decitabine (DAC), a hypomethylating agents (HMAs), plays a crucial role in the treatment of MDS [2]. However, the complete remission rate with HMAs remains low at 15–20%, and nearly half of the patients ultimately develop resistance during therapy [3, 4]. The molecular mechanisms underlying resistance to decitabine in MDS are still not fully understood [5]. With an increasing understanding of tumor pathogenesis, metabolic reprogramming, especially enhanced reductive carboxylation of glutamine or disrupted oxidative phosphorylation, is also reported to be closely associated with drug resistance in hematological malignancies [6, 7].
Herein, a combination of genome-wide CRISPR/Cas9 library screening and whole exome sequencing (WES) was employed to identify candidate genes involved in decitabine sensitivity. OGDH, which encodes a key enzyme in the tricarboxylic acid (TCA) cycle, was identified as a regulator of resistance to decitabine in MDS. The biological functions of OGDH in regulating glutamine metabolism were explored both in vitro and in vivo. Overall, we first reported that low expression of OGDH enhances reductive glutamine metabolism in MDS. The results highlight the important role of OGDH in resistance to decitabine and provide insights into potential therapeutic strategies for MDS, including targeting glutaminase (GLS).
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