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MYELODYSPLASTIC NEOPLASM

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

Leukemia volume 38, pages 2505–2509 (2024)Cite this article

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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).

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Fig. 1: Identification of OGDH as a regulator in resistance to decitabine in myelodysplastic neoplasms (MDS) cells.
Fig. 2: Effects of OGDH on glutamine metabolism reprogramming contributing to decitabine resistance in myelodysplastic neoplasms (MDS).

Data availability

The datasets used or analyzed during the current study are publicly available in the Gene Expression Omnibus (GEO) repository. The data can be accessed at the following link: https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE273914, with the accession number GSE273914.

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Acknowledgements

We thank professor Suning Chen, from the First Affiliated Hospital of Soochow University, for providing NUP98-HOXD13 mouse for this research. We thank professor Yuhui Huang, from the Cyrus Tang Hematology Center of Soochow University, and professor Sisi Chen, from Clinical Research Center of Shanghai General Hospital, for their critical reading and guidance on this study. We thank Shanghai Genechem Translational Medical Institute for help with CRISPR/Cas9 library screening. We also express our gratitude to Shanghai Applied Protein Technology Co., Ltd. for their assistance in metabolomic analysis.

Funding

This work was supported by the National Natural Science Foundation of China (82230005, 81873432, 82200133, 82200137 and 82070143), grants from the Jiangsu Province of China (BE2021645), Translational Research Grant of NCRCH (2021ZKMA01 and 2021ZKQA01) and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).

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  1. These authors contributed equally: Xiaoyan Xu, Jiaqian Qi, Hong Wang.

Authors and Affiliations

  1. National clinical research center for hematologic diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China

    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

  2. Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China

    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

  3. Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Suzhou, China

    Xiaoyan Xu, Jiaqian Qi, Hong Wang, Tingting Pan, Meng Zhou, Chengsen Cai, Yaqiong Tang, Suning Chen, Depei Wu & Yue Han

  4. State Key Laboratory of Radiation Medicine and Protection, Soochow University, Suzhou, China

    Xiaoyan Xu, Jiaqian Qi, Hong Wang, Tingting Pan, Meng Zhou, Chengsen Cai, Yaqiong Tang, Suning Chen, Depei Wu & Yue Han

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Contributions

Xiaoyan Xu designed the study, performed the research, analyzed the data, and wrote the manuscript. Jiaqian Qi and Hong Wang designed the study and analyzed the data. Ziyan Zhang, Tingting Pan, Xueqian Li, Qixiu Hou and Jingyi Yang participated in the research and data collection. Haohao Han, Mengting Guo, Meng Zhou, Chengsen Cai and Yaqiong Tang contributed to the collection of clinical samples and data analysis. Suning Chen provided NHD13 mice for our experiments. Depei Wu and Yue Han participated in the whole process of this study, supervised, and revised the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Depei Wu or Yue Han.

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The authors declare no competing interests.

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Informed consent was obtained from all patients before data collection. The study was approved by the Research Ethics Review Committee of the First Affiliated Hospital of Soochow University.

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Xu, X., Qi, J., Wang, H. et al. 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. Leukemia 38, 2505–2509 (2024). https://doi.org/10.1038/s41375-024-02377-6

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