Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Jiang, Hongmei; Wang, Yixuan; Wang, Jingjing; Wang, Sheng; He, Enyang; Guo, Jing; Xie, Ying; Wang, Jingya; Li, Xin; Peng, Ziyi; Wang, Mengqi; Hou, Jing; Liu, Zhiqiang

doi:10.1002/ctm2.744

Cited by 5 publications

(2 citation statements)

References 67 publications

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“…The methylation of Aurora A and the phosphorylation of histone methyltransferase NSD2 bilaterally form a positive regulatory loop that promotes BTZ resistance in MM cells. It should be emphasized that these observations were further confirmed in an in vivo model [ 69 ]. Similarly, Liu and co-workers demonstrated the overexpression of NSD2 in BTZ-resistant MM cells and in cells obtained from patients with the t(4;14) translocation.…”

Section: Targeting Epigenetic Mechanisms Restores Sensitivity To Btz ...mentioning

confidence: 69%

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

Kulig,

Łuczkowska,

Bakinowska

et al. 2023

Cancers

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Bortezomib (BTZ) is widely implemented in the treatment of multiple myeloma (MM). Its main mechanism of action is very well established. BTZ selectively and reversibly inhibits the 26S proteasome. More precisely, it interacts with the chymotryptic site of the 20S proteasome and therefore inhibits the degradation of proteins. This results in the intracellular accumulation of misfolded or otherwise defective proteins leading to growth inhibition and apoptosis. As well as interfering with the ubiquitin–proteasome complex, BTZ elicits various epigenetic alterations which contribute to its cytotoxic effects as well as to the development of BTZ resistance. In this review, we summarized the epigenetic alterations elicited by BTZ. We focused on modifications contributing to the mechanism of action, those mediating drug-resistance development, and epigenetic changes promoting the occurrence of peripheral neuropathy. In addition, there are therapeutic strategies which are specifically designed to target epigenetic changes. Herein, we also reviewed epigenetic agents which might enhance BTZ-related cytotoxicity or restore the sensitivity to BTZ of resistant clones. Finally, we highlighted putative future perspectives regarding the role of targeting epigenetic changes in patients exposed to BTZ.

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Section: Targeting Epigenetic Mechanisms Restores Sensitivity To Btz ...mentioning

confidence: 69%

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

Kulig,

Łuczkowska,

Bakinowska

et al. 2023

Cancers

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show abstract

“…Both in vitro and in vivo, inhibition of AURKA can induce apoptosis and cell death of MM (Shi et al, 2007;Gorgun et al, 2010). AURKA inhibitor can synergize with BTZ to kill t (4,14)-positive MM cells (Jiang et al, 2022). Several AURKA inhibitors are currently being studied in clinical trials in MM or other cancers (Dees et al, 2012;Caputo et al, 2014;Kelly et al, 2014;Long et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma

Zhang,

Wang,

Lin

et al. 2023

Front. Cell Dev. Biol.

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Background: Metabolic reprogramming is an important hallmark of cancer. Glycolysis provides the conditions on which multiple myeloma (MM) thrives. Due to MM’s great heterogeneity and incurability, risk assessment and treatment choices are still difficult.Method: We constructed a glycolysis-related prognostic model by Least absolute shrinkage and selection operator (LASSO) Cox regression analysis. It was validated in two independent external cohorts, cell lines, and our clinical specimens. The model was also explored for its biological properties, immune microenvironment, and therapeutic response including immunotherapy. Finally, multiple metrics were combined to construct a nomogram to assist in personalized prediction of survival outcomes.Results: A wide range of variants and heterogeneous expression profiles of glycolysis-related genes were observed in MM. The prognostic model behaved well in differentiating between populations with various prognoses and proved to be an independent prognostic factor. This prognostic signature closely coordinated with multiple malignant features such as high-risk clinical features, immune dysfunction, stem cell-like features, cancer-related pathways, which was associated with the survival outcomes of MM. In terms of treatment, the high-risk group showed resistance to conventional drugs such as bortezomib, doxorubicin and immunotherapy. The joint scores generated by the nomogram showed higher clinical benefit than other clinical indicators. The in vitro experiments with cell lines and clinical subjects further provided convincing evidence for our study.Conclusion: We developed and validated the utility of the MM glycolysis-related prognostic model, which provides a new direction for prognosis assessment, treatment options for MM patients.

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Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Jiang

Wang

et al. 2022

Clinical & Translational Med

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Background t(4;14)(p16;q32) cytogenetic abnormality renders high level of histone methyltransferase NSD2 in multiple myeloma (MM) patients, and predicts poor clinical prognosis, but mechanisms of NSD2 in promoting chemoresistance have not been well elucidated. Methods An epigenetics compound library containing 181 compounds was used to screen inhibitors possessing a prior synergistic effect with bortezomib (BTZ) in vitro. Molecular biology techniques were applied to uncover underlying mechanisms. Transcriptome profile assay was performed by RNA‐seq. NSG mouse‐based xenograft model and intra‐bone model were applied to qualify the synergistic effect in vivo. Results We identified an Aurora kinase A inhibitor (MLN8237) possessed a significant synergistic effect with BTZ on t(4;14) positive MM cells. Aurora A protein level positively correlated with NSD2 level, and gain‐ and loss‐of‐functions of Aurora A correspondingly altered NSD2 protein and H3K36me2 levels. Mechanistically, Aurora A phosphorylated NSD2 at S56 residue to protect the protein from cleavage and degradation, thus methylation of Aurora A and phosphorylation of NSD2 bilaterally formed a positive regulating loop. Transcriptome profile assay of MM cells with AURKA depletion identified IL6R, STC2 and TCEA2 as the downstream target genes responsible for BTZ‐resistance (BR). Clinically, higher expressions of these genes correlated with poorer outcomes of MM patients. Combined administration of MLN8237 and BTZ significantly suppressed tumour growth in LP‐1 cells derived xenografts, and remarkably alleviated bone lesion in femurs of NSG mice. Conclusions Aurora A phosphorylates NSD2 at S56 residue to enhance NSD2 methyltransferase activity and form a positive regulating loop in promoting MM chemoresistance, thus pharmacologically targeting Aurora A sensitizes t(4;14) positive MM to the proteasome inhibitors treatment. Our study uncovers a previously unknown reason of MM patients with t(4;14) engendering chemoresistance, and provides a theoretical basis for developing new treatment strategy for MM patients with different genomic backgrounds.

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Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

Cited by 5 publications

References 67 publications

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

Epigenetic Alterations as Vital Aspects of Bortezomib Molecular Action

A novel glycolysis-related gene signature for predicting the prognosis of multiple myeloma

Posttranslational modification of Aurora A‐NSD2 loop contributes to drug resistance in t(4;14) multiple myeloma

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