Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma. Issue 9 (27th January 2022)

• Record Type: Journal Article
• Authors: Feng, Xiangling; Guo, Jiaojiao; An, Gang; Wu, Yangbowen; Liu, Zhenhao; Meng, Bin; He, Nihan; Zhao, Xinying; Chen, Shilian; Zhu, Yinghong; Xia, Jiliang; Li, Xin; Yu, Zhiyong; Li, Ruixuan; Ren, Guofeng; Chen, Jihua; Wu, Minghua; He, Yanjuan; Qiu, Lugui; Zhou, Jiaxi; Zhou, Wen
• Is Part Of: Advanced science. Volume 9:Issue 9(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-01-27
• Subjects: amplification -- multiple myeloma -- NEK2 -- TP53 -- transcriptional regulation; Science -- Periodicals; 505
• DOI: 10.1002/advs.202104491
• Languages: English
• ISSNs: 2198-3844

Abstract

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. Abstract : Patients with NEK2 amplification are more prevalent in the TP53 ‐deleted subgroup of multiple myeloma (MM) and have a poor rate of survival. Dysfunctional p53 elevates NEK2 expression genetically by inducing NEK2 amplification, transcriptionally by mediating E2F8 activity, and epigenetically by increasing the expression of DNMTs. NEK2 may serve as a novel therapeutic target in aggressive MM with p53 abnormalities.