Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma
Abstract It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 an...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-03-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202104491 |
| _version_ | 1811273497939279872 |
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| author | Xiangling Feng Jiaojiao Guo Gang An Yangbowen Wu Zhenhao Liu Bin Meng Nihan He Xinying Zhao Shilian Chen Yinghong Zhu Jiliang Xia Xin Li Zhiyong Yu Ruixuan Li Guofeng Ren Jihua Chen Minghua Wu Yanjuan He Lugui Qiu Jiaxi Zhou Wen Zhou |
| author_facet | Xiangling Feng Jiaojiao Guo Gang An Yangbowen Wu Zhenhao Liu Bin Meng Nihan He Xinying Zhao Shilian Chen Yinghong Zhu Jiliang Xia Xin Li Zhiyong Yu Ruixuan Li Guofeng Ren Jihua Chen Minghua Wu Yanjuan He Lugui Qiu Jiaxi Zhou Wen Zhou |
| author_sort | Xiangling Feng |
| collection | DOAJ |
| description | Abstract It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53−/− MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle‐related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities. |
| first_indexed | 2024-04-12T23:00:13Z |
| format | Article |
| id | doaj.art-7c7949c394ef451aadd0b6e77d819754 |
| institution | Directory Open Access Journal |
| issn | 2198-3844 |
| language | English |
| last_indexed | 2024-04-12T23:00:13Z |
| publishDate | 2022-03-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj.art-7c7949c394ef451aadd0b6e77d8197542022-12-22T03:13:05ZengWileyAdvanced Science2198-38442022-03-0199n/an/a10.1002/advs.202104491Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple MyelomaXiangling Feng0Jiaojiao Guo1Gang An2Yangbowen Wu3Zhenhao Liu4Bin Meng5Nihan He6Xinying Zhao7Shilian Chen8Yinghong Zhu9Jiliang Xia10Xin Li11Zhiyong Yu12Ruixuan Li13Guofeng Ren14Jihua Chen15Minghua Wu16Yanjuan He17Lugui Qiu18Jiaxi Zhou19Wen Zhou20State Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Science & Peking Union Medical College Tianjin 300041 ChinaXiang Ya School of Public Health Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaXiang Ya School of Public Health Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaThe third Xiangya Hospital of Central South University Changsha Hunan 410013 ChinaDepartment of Pathology Changsha eighth hospital Changsha Hunan 410199 ChinaThe third Xiangya Hospital of Central South University Changsha Hunan 410013 ChinaXiang Ya School of Public Health Central South University Changsha Hunan 410028 ChinaXiang Ya School of Public Health Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaState Key Laboratory of Experimental Hematology Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Science & Peking Union Medical College Tianjin 300041 ChinaState Key Laboratory of Experimental Hematology Institute of Hematology & Blood Diseases Hospital Chinese Academy of Medical Science & Peking Union Medical College Tianjin 300041 ChinaState Key Laboratory of Experimental Hematology Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education Key Laboratory of Carcinogenesis National Health and Family Planning Commission; Department of Hematology Xiangya Hospital Central South University Changsha Hunan 410028 ChinaAbstract It has been previously shown that (never in mitosis gene A)‐related kinase 2 (NEK2) is upregulated in multiple myeloma (MM) and contributes to drug resistance. However, the mechanisms behind this upregulation remain poorly understood. In this study, it is found that amplification of NEK2 and hypermethylation of distal CpG islands in its promoter correlate strongly with increased NEK2 expression. Patients with NEK2 amplification have a poor rate of survival and often exhibit TP53 deletion, which is an independent prognostic factor in MM. This combination of TP53 knockout and NEK2 overexpression induces asymmetric mitosis, proliferation, drug resistance, and tumorigenic behaviors in MM in vitro and in vivo. In contrast, delivery of wild type p53 and suppression of NEK2 in TP53−/− MM cell lines inhibit tumor formation and enhance the effect of Bortezomib against MM. It is also discovered that inactivating p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by increased activity of cell cycle‐related genes like E2F8 and epigenetically by upregulating DNA methyltransferases. Dual defects of TP53 and NEK2 may define patients with the poorest outcomes in MM with p53 inactivation, and NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.https://doi.org/10.1002/advs.202104491amplificationmultiple myelomaNEK2TP53transcriptional regulation |
| spellingShingle | Xiangling Feng Jiaojiao Guo Gang An Yangbowen Wu Zhenhao Liu Bin Meng Nihan He Xinying Zhao Shilian Chen Yinghong Zhu Jiliang Xia Xin Li Zhiyong Yu Ruixuan Li Guofeng Ren Jihua Chen Minghua Wu Yanjuan He Lugui Qiu Jiaxi Zhou Wen Zhou Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma Advanced Science amplification multiple myeloma NEK2 TP53 transcriptional regulation |
| title | Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma |
| title_full | Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma |
| title_fullStr | Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma |
| title_full_unstemmed | Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma |
| title_short | Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma |
| title_sort | genetic aberrations and interaction of nek2 and tp53 accelerate aggressiveness of multiple myeloma |
| topic | amplification multiple myeloma NEK2 TP53 transcriptional regulation |
| url | https://doi.org/10.1002/advs.202104491 |
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