The NF-κB Activating Pathways in Multiple Myeloma

Roy, Payel; Sarkar, Uday Aditya; Basak, Soumen

doi:10.3390/biomedicines6020059

Cited by 62 publications

(58 citation statements)

References 119 publications

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“…The mutation of NF-κB pathway and the interaction with the MM microenvironment lead to the over-activation of the NF-κB pathway in MM, which promotes the transcriptional activation of downstream oncogenes, the enhanced expression of gene encoding anti-apoptotic proteins, and the suppressed expression of gene encoding proapoptotic proteins (22). The present study wondered whether cdK5 was also involved in the activation of the NF-κB pathway.…”

Section: Discussionmentioning

confidence: 83%

“…Combining dinaciclib with bortezomib cooperatively suppresses the nuclear factor (NF)-κB signaling pathway in MM cells. It is well established that the activation of NF-κB pathway is found in numerous tumors, including MM (22). One of the main anti-myeloma mechanisms of bortezomib is to inhibit the activation of the NF-κB pathway by disturbing the ubiquitin-proteasome degradation of the inhibitor IκBα of the NF-κB pathway (23).…”

Section: Effect Of Dinaciclib On the Viability Of MM Cells In Vitromentioning

confidence: 99%

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CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Tang

Cen

et al. 2020

Int J Mol Med

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The emergence of new drugs is a major feature of the treatment history of multiple myeloma (MM), which also reflects the current incurability of MM. As a unique member of cyclin dependent kinase (cdK) family, cdK5 participates in numerous tumorigenic or non-tumorigenic processes. The aim of this study is to investigate the effects of cdK5 on the viability of MM cells and bortezomib resistance using western blotting, immunohistochemistry, transient transfection, MTT assays, cell cycle analysis, apoptosis assays and a myeloma xenograft mouse model. The present study found that MM patients with high CDK5 expression in the bone marrow do not respond well to bortezomib, have higher DS stage and worse prognosis. Genetic and pharmacological (dinaciclib) inhibition of CDK5 triggers MM cell viability inhibition. Dinaciclib induces G2/M arrest and apoptosis of MM cells.In vivo experiments with myeloma xenograft mice indicate that dinaciclib significantly reduces the volume of tumors with good tolerance. Dinaciclib combined with bortezomib exerts a synergistic anti-myeloma activity accompanied by inhibiting the activation of the nuclear factor-κB pathway. This study demonstrates the important role of cdK5 in the pathogenesis, viability, prognosis and resistance to bortezomib of MM, laying a solid theoretical foundation for further clinical use of CDK5 inhibitors.

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Section: Discussionmentioning

confidence: 83%

Section: Effect Of Dinaciclib On the Viability Of MM Cells In Vitromentioning

confidence: 99%

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Tang

Cen

et al. 2020

Int J Mol Med

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“…Over the past decades, intensive research addressing the role to the BM-ME in hematological malignancies clearly demonstrated that the accessory cells of the BM can support the survival and proliferation of leukemia and MM-cells not only by promoting growth but also by inhibiting apoptosis [63]. The anti-apoptotic effects of the BM-ME are primarily established by upregulation of anti-apoptotic regulatory proteins via the stimulation of RAS/MEK/ERK, JAK/STAT3, PI3K/Akt as well as the NF-kB signaling pathways [64][65][66]. For instance, multiple members of the BCL2 family of proteins BCL-2, BCL-X L and MCL-1, which are known to negatively regulate BAK-and BAX-mediated mitochondrial membrane destabilization [67], are significantly upregulated by activation of the above mentioned signaling pathways via several soluble factors produced by BM MSCs such as IL-6, IGF-1 or VEGF [68].…”

Section: Inhibition Of Apoptosis By the Bm-mementioning

confidence: 99%

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Holthof

Mutis

2020

Cancers

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The power of immunotherapy in the battle of Multiple Myeloma (MM) started with allogeneic stem cell transplantation, and was rediscovered with immunomodulatory drugs and extended with the outstanding results achieved with targeted antibodies. Today, next to powerful antibodies Elotuzumab and Daratumumab, several T-cell-based immunotherapeutic approaches, such as bispecific antibodies and chimeric antigen receptor-transduced T-cells (CAR T-cells) are making their successful entry in the immunotherapy arena with highly promising results in clinical trials. Nonetheless, similar to what is observed in chemotherapy, MM appears capable to escape from immunotherapy, especially through tight interactions with the cells of the bone marrow microenvironment (BM-ME). This review will outline our current understanding on how BM-ME protects MM-cells from immunotherapy through immunosuppression and through induction of intrinsic resistance against cytotoxic effector mechanisms of T- and NK-cells.

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“…53 These ligands stimulate cells of the microenvironment, such as MDSCs 54 , to ultimately produce ligands such as S100A8, S100A9, TNF, and IL-1B, all of which stimulate receptor-mediated NF-kB signaling and thus complete a circuit. 51,53,55–58 The genes of this circuit belong to Pr-134, suggesting that NF-kB signaling is a driver of microenvironment-induced resistance.…”

Section: Discussionmentioning

confidence: 99%

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

Wall

Turkarslan

et al. 2020

Preprint

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38Despite recent advancements in the treatment of multiple myeloma (MM), nearly all patients 39 ultimately relapse and many become refractory to their previous therapies. Although many 40 therapies exist with diverse mechanisms of action, it is not yet clear how the differences in MM 41 biology across patients impacts the likelihood of success for existing therapies and those in the 42 pipeline. Therefore, we not only need the ability to predict which patients are at high risk for 43 disease progression, but also a means to understand the mechanisms underlying their risk. We 44 hypothesized that knowledge of the biological networks that give rise to MM, specifically the 45 transcriptional regulatory network (TRN) and the mechanisms by which mutations impact gene 46 regulation, would enable improved predictions of disease progression and actionable insights for 47 treatment. Here we present a method to infer TRNs from multi-omics data and apply it to the 48 generation of a MM TRN that links chromosomal abnormalities and somatic mutations to 49 downstream effects on gene expression via perturbation of transcriptional regulators. We find that 50 141 genetic programs underlie the disease and that the activity profile of these programs fall into 51 one of 25 distinct transcriptional states. These transcriptional signatures prove to be more 52 predictive of outcomes than do mutations and reveal plausible mechanisms for relapse, including 53 the establishment of an immuno-suppressive microenvironment. Moreover, we observe subtype-54 specific vulnerabilities to interventions with existing drugs and motivate the development of new 55 targeted therapies that appear especially promising for relapsed refractory MM. 56 57 Introduction 58 59 Multiple Myeloma (MM) is a cancer of malignant plasma cells in the bone marrow (BM) that has 60 a prevalence of approximately 86,000 new cases per year. 1 Several clinical subtypes of MM have 61 been established on the basis of characteristic cytogenetic features, including various 62 translocations, gain or loss of chromosomal arms, deletion of specific chromosomes, and 63 hyperdiploidy. 2-4 Accordingly, MM is a complex disease of great heterogeneity that exhibits64 subtype-specific drivers of progression. 5,6 Efforts to better characterize the biology and 65 therapeutic vulnerabilities of MM have increased exponentially in recent years, as can be seen 66 from the number of research articles, clinical trials, and public availability of matched genomic, 67 transcriptomic, and patient data. However, the myriad combinations of chromosomal aberrations 68 and somatic mutations, coupled with the complex dependence of MM progression on the BM 69 microenvironment, have precluded a mechanistic understanding of the disease on a patient-70 specific level. 72The 5-year survival rate of MM is approximately 50% 7 , which is nearly double what it was in the 73 late 1980s. 8 The reason for the improved outcomes is a series of therapeutic advances that 74 include the introduction of autologous stem cell t...

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The NF-κB Activating Pathways in Multiple Myeloma

Cited by 62 publications

References 119 publications

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

CDK5 inhibition in�vitro and in vivo induces cell death in�myeloma and overcomes the obstacle of bortezomib resistance

Challenges for Immunotherapy in Multiple Myeloma: Bone Marrow Microenvironment-Mediated Immune Suppression and Immune Resistance

Genetic program activity delineates risk, relapse, and therapy responsiveness in Multiple Myeloma

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