ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling
Abstract 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 gen...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2022-09-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-022-01170-7 |
| _version_ | 1811200721625808896 |
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| author | Guangjie Zhao Shuang Li Qian Wang Wanlin Wu Xuewei Fu Chen Zhu Wei Wang Xiaoqin Wang |
| author_facet | Guangjie Zhao Shuang Li Qian Wang Wanlin Wu Xuewei Fu Chen Zhu Wei Wang Xiaoqin Wang |
| author_sort | Guangjie Zhao |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-12T02:08:11Z |
| format | Article |
| id | doaj.art-b4e72927249f4e6d94a27dbd7a80f2ec |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-12T02:08:11Z |
| publishDate | 2022-09-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-b4e72927249f4e6d94a27dbd7a80f2ec2022-12-22T03:52:28ZengNature Publishing GroupCell Death Discovery2058-77162022-09-018111010.1038/s41420-022-01170-7ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signalingGuangjie Zhao0Shuang Li1Qian Wang2Wanlin Wu3Xuewei Fu4Chen Zhu5Wei Wang6Xiaoqin Wang7Department of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Shanghai General Hospital, Shanghai Jiao Tong UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityDepartment of Hematology, Huashan Hospital, Fudan UniversityAbstract 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.https://doi.org/10.1038/s41420-022-01170-7 |
| spellingShingle | Guangjie Zhao Shuang Li Qian Wang Wanlin Wu Xuewei Fu Chen Zhu Wei Wang Xiaoqin Wang ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling Cell Death Discovery |
| title | ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling |
| title_full | ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling |
| title_fullStr | ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling |
| title_full_unstemmed | ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling |
| title_short | ABAT gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through CXCR4/mTOR signaling |
| title_sort | abat gene expression associated with the sensitivity of hypomethylating agents in myelodysplastic syndrome through cxcr4 mtor signaling |
| url | https://doi.org/10.1038/s41420-022-01170-7 |
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