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 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.

Intestinal Klebsiella pneumoniae Contributes to Pneumonia by Synthesizing Glutamine in Multiple Myeloma

“…Total RNA was extracted from whole lung cells and WI38 cells using Trizol. cDNA was synthesized from 1 μg total RNA and real-time qPCR for TNF-α, IL-1β, and IL-6 was performed as previously presented [ 22 ]. The primer sequences were provided in Table S1 .…”

NAIRscore as a biomarker for the quality of immune response to neoantigens is related with an increased overall survival in multiple myeloma

“… 1 , 2 In recent decades, many explorations and advances in therapeutics have prolonged the survival for most patients with MM, but MM remains incurable and prone to relapse in the vast majority of cases. 3 , 4 , 5 , 6 The treatment of MM remains challenging, especially for relapsed/refractory patients. Due to clinical and pathological heterogeneity, response and survival in MM treatment vary to prognostic risk factors, such as disease stage at diagnosis and cytogenetic abnormalities.…”

NEK2, a promising target in TP53 mutant cancer

“…In the current issue of Adv Sci 2022, Feng et al expand the significance of TP53 loss to drug resistance through co-regulating oncogene NEK2 amplification/gene overexpression with multiple myeloma (MM) as a disease model. 5 In this paper, the authors set out the study with systematic identification of the correlation between TP53 genetic lesion and amplification/overexpression of NEK2 in MM through data mining of public available datasets. This led to the discovery of co-occurrence between TP53 deletion and NEK2 amplification/ overexpression, which is significantly associated with poor overall survival in MM.…”

“…KRAS hyper-activation leads to cell replicative senescence, which could be overcome by lesions in TP53, escaping immune clearance surveillance and promoting tumorigenesis. In the current issue of Adv Sci 2022, Feng et al expand the significance of TP53 loss to drug resistance through co-regulating oncogene NEK2 amplification/gene overexpression with multiple myeloma (MM) as a disease model 5 …”

“…In the current issue of Adv Sci 2022, Feng et al expand the significance of TP53 loss to drug resistance through co-regulating oncogene NEK2 amplification/gene overexpression with multiple myeloma (MM) as a disease model. 5 …”