The impact of NF-κB signaling on pathogenesis and current treatment strategies in multiple myeloma

Vrábel, Dávid; Pour, Luděk; Ševčı́ková, Sabina

doi:10.1016/j.blre.2018.11.003

Cited by 99 publications

(103 citation statements)

References 169 publications

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“…Previous studies have found that activating mutations of NF-κB pathway have been frequently observed in MM with nearly 50% of MMCLs and most primary MM samples observed to have increased levels of NF-κB activity [41]. Given the importance of NF-κB pathway in MM pathogenesis, the positive regulation of NF-κB signaling by G9a in MM may have profound significance on understanding and treating MM [72]. Specifically, work here shows that G9a can positively regulate expression of RelB, which together with p52 is the main member of non-canonical NF-κB pathway.…”

Section: Discussionmentioning

confidence: 99%

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma

et al. 2020

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Background: Multiple myeloma is an incurable hematological malignancy characterized by a heterogeneous genetic and epigenetic landscape. Although a number of genetic aberrations associated with myeloma pathogenesis, progression and prognosis have been well characterized, the role of many epigenetic aberrations in multiple myeloma remain elusive. G9a, a histone methyltransferase, has been found to promote disease progression, proliferation and metastasis via diverse mechanisms in several cancers. A role for G9a in multiple myeloma, however, has not been previously explored. Methods: Expression levels of G9a/EHMT2 of multiple myeloma cell lines and control cells Peripheral Blood Mononuclear Cells (PBMCs) were analyzed. Correlation of G9a expression and overall survival of multiple myeloma patients were analyzed using patient sample database. To further study the function of G9a in multiple myeloma, G9a depleted multiple myeloma cells were built by lentiviral transduction, of which proliferation, colony formation assays as well as tumorigenesis were measured. RNA-seq of G9a depleted multiple myeloma with controls were performed to explore the downstream mechanism of G9a regulation in multiple myeloma. Results: G9a is upregulated in a range of multiple myeloma cell lines. G9a expression portends poorer survival outcomes in a cohort of multiple myeloma patients. Depletion of G9a inhibited proliferation and tumorigenesis in multiple myeloma. RelB was significantly downregulated by G9a depletion or small molecule inhibition of G9a/GLP inhibitor UNC0642, inducing transcription of proapoptotic genes Bim and BMF. Rescuing RelB eliminated the inhibition in proliferation and tumorigenesis by G9a depletion. Conclusions: In this study, we demonstrated that G9a is upregulated in most multiple myeloma cell lines. Furthermore, G9a loss-of-function analysis provided evidence that G9a contributes to multiple myeloma cell survival and proliferation. This study found that G9a interacts with NF-κB pathway as a key regulator of RelB in multiple myeloma and regulates RelB-dependent multiple myeloma survival. G9a therefore is a promising therapeutic target for multiple myeloma.

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Section: Discussionmentioning

confidence: 99%

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma

et al. 2020

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“…For example, the increase in p-IκBα and the activation of NF-κB p65 were detected in monocrotaline-induced pulmonary hypertensive rats, mice with Alzheimer's disease, rats with autoimmune myocarditis, and gastric cancer caused by Helicobacter pylori (Nozaki et al, 2005;Feng et al, 2017;Zhang et al, 2017;Fang et al, 2019). As a key regulator of the NF-κB signaling pathway, IκBα has attracted increasing research attention and its post-translational modification provides new therapeutic opportunities for diseases related to abnormal NF-κB activation (Vrábel et al, 2019).…”

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

“…For instance, proteasome inhibitors have been clinically used in the treatment of multiple myeloma (MM) (Tundo et al, 2020). Previous studies have demonstrated that the dysregulation of NF-κB pathway contribute to the development and clinical manifestations of MM via NF-κB target genes, including the growth factor interleukin-6 and insulin-like growth factor-1, cell cycle regulators cyclin D and c-Myc, and pro-angiogensis factors vascular endothelial growth factor-C and placental growth factor (Vrábel et al, 2019). Because the ubiquitination and subsequent degradation of IκBα in the proteasome are predominant mechanisms of the NF-κB pathway activation (Feng et al, 2017;Tundo et al, 2020), bortezomib, a reversible proteasome inhibitor, was used in the treatment of MM.…”

Section: Therapeutic Opportunities Based On Iκbα Modulationmentioning

confidence: 99%

Post-translational Modifications of IκBα: The State of the Art

Wang

Peng

Huang

et al. 2020

Front. Cell Dev. Biol.

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The nuclear factor-kappa B (NF-κB) signaling pathway regulates a variety of biological functions in the body, and its abnormal activation contributes to the pathogenesis of many diseases, such as cardiovascular and respiratory diseases and cancers. Therefore, to ensure physiological homeostasis of body systems, this pathway is strictly regulated by IκBα transcription, IκBα synthesis, and the IκBα-dependent nuclear transport of NF-κB. Particularly, the post-translational modifications of IκBα including phosphorylation, ubiquitination, SUMOylation, glutathionylation and hydroxylation are crucial in the abovementioned regulatory process. Because of the importance of the NF-κB pathway in maintaining body homeostasis, understanding the post-translational modifications of IκBα can not only provide deeper insights into the regulation of NF-κB pathway but also contribute to the development of new drug targets and biomarkers for the diseases.

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“…The constitutive activation of NF-kB is mainly responsible for the stroma-independent growth of MM cells at this stage, because NF-kB-dependent expression of adhesion molecules, such as the VLA-4 integrin, is sustained by direct contact and/or stroma-derived cytokines. As a mechanism of constitutive activation of NF-kB, homozygous deletion of the genes encoding inhibitors of the NF-kB pathways is often detected in MM cells at this stage (10-15% in total), including BIRC2/3 on chromosome 11 (~ 7%), TRAF3 on chromosome 14 (~ 3%) and CYLD on chromosome 16 (~ 3%) [45]. Terminal-stage myeloma also shows massive structural abnormalities of chromosomes, such as complex translocations involving the 8q24 locus, in which the c-Myc gene is located [46], duplication of the long arm of chromosome 1 (1q gain), and deletions of 1p32 or 17p13 [47][48][49].…”

Section: Genomic Changes During the Terminal Phase Of MMmentioning

confidence: 99%

Molecular basis of clonal evolution in multiple myeloma

Furukawa

Kikuchi

2020

Int J Hematol

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The treatment outcome of multiple myeloma (MM) is worse than expected from the average numbers of non-synonymous mutations, which are roughly correlated with the prognosis of cancer patients. The refractoriness of MM may be ascribed to the complex genomic architecture and clonal behavior of the disease. In MM, disease progression is accomplished by branching patterns of subclonal evolution from reservoir clones with a propagating potential and/or the emergence of minor clones, which already exist at the MGUS stage and outcompete other clones through selective pressure mainly by therapeutic agents. Each subclone harbors novel mutations and distinct phenotypes including drug sensitivities. In general, mature clones are highly sensitive to proteasome inhibitors (PIs), whereas immature clones are resistant to PIs but could be eradicated by immunomodulatory drugs (IMiDs). The branching evolution is a result of the fitness of different clones to microenvironment and their evasion of immune surveillance; therefore, IMiDs are effective for MM with this pattern of evolution. In contrast, ~ 20% of MM evolve neutrally in the context of strong oncogenic drivers, such as high-risk IgH translocations, and are relatively resistant to IMiDs. Further understanding of the genomic landscape and the pattern of clonal evolution may contribute to the development of more effective treatment strategies for MM.

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The impact of NF-κB signaling on pathogenesis and current treatment strategies in multiple myeloma

Cited by 99 publications

References 169 publications

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma

Frequent upregulation of G9a promotes RelB-dependent proliferation and survival in multiple myeloma

Post-translational Modifications of IκBα: The State of the Art

Molecular basis of clonal evolution in multiple myeloma

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