Cytokines and Signal Transduction in Multiple Myeloma

2012 ◽  
pp. 535-546 ◽  
Author(s):  
Dharminder Chauhan ◽  
Kenneth C. Anderson
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma

Impact of Natural Dietary Agents on Multiple Myeloma Prevention and Treatment: Molecular Insights and Potential for Clinical Translation

2020 ◽  
Vol 27 (2) ◽  
pp. 187-215 ◽  
Author(s):  
Lavinia Raimondi ◽  
Angela De Luca ◽  
Gianluca Giavaresi ◽  
Agnese Barone ◽  
Pierosandro Tagliaferri ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Natural Products ◽  
Bone Disease ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Signal Transduction Pathways ◽  
Pharmacologically Active ◽  
Dietary Agents

: Chemoprevention is based on the use of non-toxic, pharmacologically active agents to prevent tumor progression. In this regard, natural dietary agents have been described by the most recent literature as promising tools for controlling onset and progression of malignancies. Extensive research has been so far performed to shed light on the effects of natural products on tumor growth and survival, disclosing the most relevant signal transduction pathways targeted by such compounds. Overall, anti-inflammatory, anti-oxidant and cytotoxic effects of dietary agents on tumor cells are supported either by results from epidemiological or animal studies and even by clinical trials. : Multiple myeloma is a hematologic malignancy characterized by abnormal proliferation of bone marrow plasma cells and subsequent hypercalcemia, renal dysfunction, anemia, or bone disease, which remains incurable despite novel emerging therapeutic strategies. Notably, increasing evidence supports the capability of dietary natural compounds to antagonize multiple myeloma growth in preclinical models of the disease, underscoring their potential as candidate anti-cancer agents. : In this review, we aim at summarizing findings on the anti-tumor activity of dietary natural products, focusing on their molecular mechanisms, which include inhibition of oncogenic signal transduction pathways and/or epigenetic modulating effects, along with their potential clinical applications against multiple myeloma and its related bone disease.

RNA interference for multiple myeloma therapy: targeting signal transduction pathways

2015 ◽  
Vol 20 (1) ◽  
pp. 107-121 ◽  
Author(s):  
Jianfeng Guo ◽  
Sharon L McKenna ◽  
Michael E O’Dwyer ◽  
Mary R Cahill ◽  
Caitriona M O’Driscoll
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Rna Interference ◽  
Signal Transduction Pathways ◽  
Targeting Signal

Interleukin-6–dependent gene expression profiles in multiple myeloma INA-6 cells reveal a Bcl-2 family–independent survival pathway closely associated with Stat3 activation

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 242-251 ◽  
Author(s):  
Katja Brocke-Heidrich ◽  
Antje K. Kretzschmar ◽  
Gabriele Pfeifer ◽  
Christian Henze ◽  
Dennis Löffler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Multiple Myeloma ◽  
Interleukin 6 ◽  
Target Genes ◽  
B Lymphocyte ◽  
Expression Profiles ◽  
B Cell Lymphoma ◽  
Myeloma Cells ◽  
Survival Pathway

Abstract Interleukin 6 (IL-6) is a growth and survival factor for multiple myeloma cells. As we report here, the IL-6–dependent human myeloma cell line INA-6 responds with a remarkably rapid and complete apoptosis to cytokine withdrawal. Among the antiapoptotic members of the B-cell lymphoma-2 (Bcl-2) family of apoptosis regulators, only myeloid cell factor-1 (Mcl-1) was slightly induced by IL-6. Overexpression studies demonstrated, however, that IL-6 does not exert its survival effect primarily through this pathway. The IL-6 signal transduction pathways required for survival and the target genes controlled by them were analyzed by using mutated receptor chimeras. The activation of signal transducer and activator of transcription 3 (Stat3) turned out to be obligatory for the survival of INA-6 cells. The same held true for survival and growth of XG-1 myeloma cells. Gene expression profiling of INA-6 cells by using oligonucleotide microarrays revealed many novel IL-6 target genes, among them several genes coding for transcriptional regulators involved in B-lymphocyte differentiation as well as for growth factors and receptors potentially implicated in autocrine or paracrine growth control. Regulation of most IL-6 target genes required the activation of Stat3, underscoring its central role for IL-6 signal transduction. Taken together, our data provide evidence for the existence of an as yet unknown Stat3-dependent survival pathway in myeloma cells.

Genomic Analysis of High Hyperdiploid Acute Lymphoblastic Leukemia and Hyperdiploid Multiple Myeloma Suggests Differential Gene Dosage Effect on Expression and Provide Clues to Preferential Selection of Recurrently Trisomic Chromosomes.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3006-3006
Author(s):  
Wee-Joo Chng ◽  
Scott Van Wier ◽  
Gregory Ahmann ◽  
Tammy Price-Troska ◽  
Kim Henderson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Signal Transduction ◽  
Multiple Myeloma ◽  
Protein Synthesis ◽  
Differentially Expressed Genes ◽  
Gene Dosage ◽  
Lymphoblastic Leukemia ◽  
Differentially Expressed ◽  
Expression Data ◽  
Gene Dosage Effect

Abstract Hyperdiploid (>48 chromosomes) multiple myeloma (H-MM) and high hyperdiploid (>50 chromosomes) acute lymphoblastic leukemia (H-ALL) are characterized by aneuploidy and multiple recurrent trisomies (chromosome 3,5,7,9,11,15,19 for H-MM and chromosomes X,4,6,10,14,17,18,21 for H-ALL). Little is known about the oncogenic events, consequences of the trisomies and reasons for the different recurrent trisomies. In an attempt to answer these questions, we undertook a combined gene expression and network/pathway analysis approach. Gene expression data was generated using the Affymetrix U133A chip (Affymetrix, Santa Clara, Ca) for 53 H-MM and 37 non-hyperdiploid MM (NH-MM) cases using CD138-enriched plasma-cell RNA. Gene expression data using the same chip for ALL was obtained from previous published data (Ross ME et al Blood2004; 104: 3679–3687). Analysis was performed using Genespring 7 (Agilent Technologies, Palo Alto, CA). By comparing the median expression of all genes on each chromosome between H-MM/H-ALL and their non-hyperdiploid counterparts (NH-MM and NH-ALL) for the 23 chromosomes (excluding Y), one can clearly identify the commonly trisomic chromosomes in H-ALL and H-MM. However, the relationship of gene expression was highly variable for H-MM and NH-MM as compared to H-ALL and NH-ALL which tended to have expression ratios close to 1 for the non-trisomic chromosomes. Sixty-nine percent of the differentially expressed genes generated by ANOVA analysis (p<0.001) in H-ALL were on the commonly trisomic chromosomes and were upregulated whereas the corresponding figure in H-MM is 40%. These similarities and differences probably reflect both an overall gene dosage effect and the different complexities of the karyotypes of H-MM and H-ALL compared to NH-MM and NH-ALL respectively (MM karyotypes are more complex, hence difference between H and NH-MM is greater and less confined to the trisomic chromosomes). We next performed network analysis using a curated web-based software (MetaCore, GeneGo Inc, St Joseph, MI) using the 2 sets of differentially expressed genes. Majority of genes differentially expressed in H-MM are involved in mRNA translation/protein synthesis whereas the genes differentially expressed in H-ALL were mainly involved in signal transduction. Therefore the transcriptional program that characterize the difference between H and NH-MM/ALL seem to recapitulate normal cellular function: protein synthesis in the mature secretory plasma cells and signal transduction in response to cytokines in a differentiating early-B cell. However, due to the concurrent deregulation of many genes on these trisomic chromosomes, these and other cellular programs are deregulated resulting in malignant transformation. We also intersected the 2 lists of differentially expressed genes to find genes that are up- or downregulated in both H-MM and H-ALL relative to the NH tumors. Thirteen genes including interferon response genes (TNFSF10, MX1, ZNF185) and transcription factors like RUNX1 were upregulated, whereas 13 genes including a cancer testis antigen gene (MAGED4) were downregulated in both H-MM and H-ALL. These genes may point to common oncogenic mechanisms.

Valproic Acid Induces Non Apoptotic Cell Death in Myeloma Cells and Cell Lines.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5130-5130
Author(s):  
Chantal Schwartz ◽  
Valérie Palissot ◽  
Rene I. Brons ◽  
Bernadette Leners ◽  
Manon Bosseler ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Valproic Acid ◽  
Cell Death ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Signal Transduction Pathways ◽  
Apoptosis Pathway ◽  
Intrinsic Apoptosis Pathway ◽  
In Cells

Abstract Multiple myeloma is, despite the emergence of new treatment strategies in recent years, still a lethal disease in 2005. Over the last several years, significant insights into the dysregulation of various signal transduction pathways of MM have emerged and have evolved the development of new agents. Histone deacetylase inhibitors as valproic acid are compounds that inhibit HDACs enzymes that, in conjunction with histone acetylases, regulate the acetylation state of histones and, by extension, the conformational status of chromatin. VPA is clinically known to be used in treatment of different types of epileptic disease. Effects and signal transduction pathways of cell death have been studied in cells harvested and purified from routine bone marrow aspirates of several patients with multiple myeloma, as well as on myeloma cell lines (OPM2, U266) treated with a physiologic dose range of valproic acid (1–4 mM). We observe significant in vitro toxicity starting at doses of 1 mM for 24h in cell lines as well as in patient cells using an XTT based cytotoxicity assay. The question we adressed was the mechanisms by which the MM died. Flow cytometric analysis with PI / Annexin V staining does not show apoptosis features, nor do TUNEL staining or DNA fragmentation assays, suggesting non activation of the intrinsic apoptosis pathway. In contrast, cell morphology of treated cells stained with May-Gruenwald-Giemsa staining show increase in multinucleated giant cells. Multinucleation has often been described in cells which die through mitotic catastrophe. Further experiments exploring this hypothesis will be conducted. Effect of 48h valproic ac on myeloma cell lines Effect of 48h valproic ac on myeloma cell lines Effect of 48h valproic ac on CD138 cells from myeloma patients Effect of 48h valproic ac on CD138 cells from myeloma patients

Blockage of TRAF6 by Dominant Negative Peptides to Inhibit Multiple Myeloma (MM) Cell Proliferation and Osteoclast Formation through NF-κB, JNK and AKT Signal Transduction Pathways

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4068-4068 ◽  
Author(s):  
Mingjie Li ◽  
Eric Sanchez ◽  
Cathy Wang ◽  
Megan Schultz ◽  
Jessica Wang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Bone Resorption ◽  
Tumor Cells ◽  
Cell Apoptosis ◽  
Osteoclast Formation ◽  
Dominant Negative ◽  
Control Group ◽  
Affinity Column

Abstract Abstract 4068 Several members of the tumor necrosis factor receptor-associated factor (TRAF) family, including TRAF1, TRAF2, TRAF3, TRAF5, and TRAF6 have been implicated in regulating signal transduction from various TRAF family members. However, the unique biological function of TRAF6 is largely determined by its TRAF-C domain, which does not interact with peptide motifs that are recognized by TRAF1, -2, -3 or -5. We have reported inhibition of MM cell proliferation and increase of apoptosis through regulation of the NF-κB and JNK pathways through silencing TRAF6 C-domain mRNA and the dominant negative peptide expression vector (Chen H. et al, Oncogene, 2006; Li M. et al, Blood 2009). TRAF6 have been recently found as a ligase for Akt ubiquitination (Yang WL et al, Science, 2009). Akt signaling plays a central role in many biological functions, such as cell proliferation and apoptosis. In this study, we first investigated whether TRAF6 is over-expressed in MM tumor cells. Twelve MM fresh bone marrow (BM) aspirates derived from MM patients were assessed using Western blot analysis and immunohistochemical staining with anti-TRAF6 antibody. We found that TRAF6 protein was highly expressed in tumor cells from MM patients compared to normal human BM samples. Based on TRAF6, CD40, and RANKL sequences and crystal structures, we targeted the TRAF6 C-domain binding residues. We found that TRAF6 dominant negative binding peptide (TRAF6dn) significantly inhibited MM cell proliferation maximally at 72 hours using the MTS cell proliferation assay whereas effects on inducing MM cell apoptosis were most prominent at 48 hours as assessed with Annexin V staining with flow cytometric analysis. The decrease in cell proliferation and increase in cell apoptosis occurred in a concentration peptide-dependent fashion. Furthermore, phosphorylation of both AKT and NF-κB were also reduced using our human TRAF6dn or decoy peptides. We also examined the effect of the TRAF6dn peptide on the JNK pathway since this signaling pathway is also associated with cell cycle effects in MM. We measured JUN kinase kinase (JNKK), which activates the MAP kinase homologues SAPK and JNK in response to IL-1 receptor stimulation. The results showed that the phosphorylation of JNKK is markedly reduced after treatment with the TRAF6dn peptide. Furthermore, we examined c-Jun, a component of the transcription factor complex AP-1, which binds and activates transcription at TRE/AP-1 elements. We evaluated the effect of TRAF6dn peptide on osteoclast formation using cells from human monocytes isolated by anti-CD14 micro-bead affinity column from MM patients' BM or peripheral blood mononuclear cells. The monocytes were cultured on slide-culture dishes (2 × 105 cells/well).We found TRAF6dn markedly inhibited osteoclast cell formation from monocytes induced with RANKL and mCSF in a concentration- dependent fashion compared with a control group using tartrate resistant acid phosphatase staining. We further assessed whether TRAF6dn can reduce bone resorption using a dentin bone resorption assay. BM-derived monocytes were isolated as above and were cultured on dentin bone slides (4 × 105 cells/slide). The cells treated with a TRAF6dn peptide or the control peptide, were incubated with 50ng/ml RANKL and 10ng/ml MCSF. All cells were cultured for 21 days. It was found that TRAF6dn significantly inhibited lacunar resorption in a concentration-dependent fashion. These studies suggest that TRAF6 is over-expressed in MM and our TRAF6dn peptide inhibits many signaling pathways critical to the growth of MM and formation of osteoclasts resulting in marked anti-MM effects and reduction in osteoclast formation resulting in marked inhibition of bone resorption. Thus, this novel approach may offer a new therapeutic approach to both treat multiple myeloma and reduce the clinical consequences resulting from enhanced bone loss that commonly occur in these patients. Disclosures: No relevant conflicts of interest to declare.

Potentiated Phospho-Protein Network Profiling of Multiple Myeloma Cell Lines and Primary Patient Samples by Multi-Parameter Flow Cytometry.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1505-1505
Author(s):  
Zhi Hua Li ◽  
Peter Leif Bergsagel ◽  
Sue Chow ◽  
David Hedley ◽  
Suzanne Trudel
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Myeloma Cell ◽  
Molecular Heterogeneity ◽  
Fish Analysis ◽  
Molecular Abnormalities ◽  
Signal Transduction Inhibitors

Abstract The importance of aberrant signal transduction in the development and progression of cancers including multiple myeloma (MM) is well recognized, although the detailed regulation of signaling networks in relation to oncogenic mutations remains incompletely understood. However, this subject is becoming increasing relevant to clinical oncology due the rapid development of biological-based therapies that can target signaling pathways. Analytical methods that can be applied to clinical samples to measure complex populations of cells and phenotype them for multiple activation states are now feasible due to the recent advances in intracellular signal techniques, flow cytometry and phospho-antibodies. Using multi-parameter flow cytometry, we monitored phospho-protein responses to activators/cytokines and signal transduction inhibitors in a panel of 14 extensively characterized human MM cell lines with heterogeneous molecular abnormalities. A panel of 4-phospho-specific antibodies: anti-pS6, anti-ERK1/2, anti-pAKT and anti-pSTAT3 that represent downstream target genes of signaling pathways known to play central roles in myelomagenesis were used in the initial analysis. Sixteen conditions (basal, inhibitor, activator alone, activator and inhibitor) were studied to generated 64 readouts designed to survey altered signal transduction in the 14 cell lines. We collected data on unstimulated cells and cells stimulated for 7–10 min with IL-6, IGF-1 or FGF or cells inhibited with the signal transduction inhibitors U0126 (MEK), rapamycin (mTOR) or LY294002 (PI3-K). Repeat measurements were collected and the technique and monoclonal antibodies displayed a high level of reproducibly. In contrast, the basal, cytokine and inhibitor responses between cell lines varied considerably reflecting the molecular heterogeneity at the level of signaling responses. The protocols that have been refined and validated in myeloma cell lines are now being applied to primary bone marrow samples from MM patients. Although the same size thus far is small, phospho-protein responses among primary CD138 positive myeloma cells show considerable induction and variance of AKT, MAPK, STAT3 and pS6 phosphorylation. In some MM tumor samples treatment with inhibitors suggest constitutive activation of these signaling pathways while in others the nodes remain activable with phosphorylation above the basal state following stimulation. The data further suggests that MAPK phosphorylation following aFGF stimulation displays significant variance among MM samples and correlates with the detection of t(4;14) translocation by FISH analysis. Additional samples are being assessed and correlation of phospho-protein responses with clinical parameters and cytogenetics will be reported. The data demonstrate that multi-parameter flow cytometry can be applied to myeloma tumor samples to study the phospho-proteome and that considerable heterogeneity exists at the level of signaling responses.

P/E Selectins and Their Ligand PSGL-1 Are Crucial for Macrophage-Mediated Multiple Myeloma Chemoresistance

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 130-130 ◽  
Author(s):  
Yuhuan Zheng ◽  
Jing Yang ◽  
Jianfei Qian ◽  
Shino Hanabuchi ◽  
Zhiqiang Liu ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Multiple Myeloma ◽  
Conflicts Of Interest ◽  
Mechanistic Study ◽  
Accessory Cell ◽  
Cell Contact ◽  
Src Family Kinase ◽  
Coculture Condition

Abstract Abstract 130 Multiple myeloma (MM) bone marrow (BM) provides a homing microenvironment, which is important for tumor development, growth, proliferation, migration and chemoresistance. Our previous research has shown that macrophages (MΦ) are associated with malignant BM and confer MM cell chemoresistance in vitro. Based on these findings, we designed mechanistic studies to elucidate MΦ-mediated MM chemoresistance. MΦ protected MM cells from different chemotherapeutics, such as bortezomib, doxorubicin, dexamethasone, melphalan, or their combination-induced apoptosis. Cell-to-cell contact was crucial for such protection. Under a coculture condition, MΦ protected MM cells with wide ranging MM/MΦ ratio. Inhibition of phagocytosis did not affect the protection. An experiment examining MM patients' BM showed that MΦ was a dominant accessory cell population in patients' BM. Patients PBMC-derived MΦ or primary MΦ isolated from patient BM had protective activity. Further mechanistic study showed that surface molecules, such as P/E selectins (on MΦ) and their ligand PSGL-1 (on MM cells), were important for MΦ-mediated MM chemoresistance. Blockade antibodies against either P/E selectins or PSGL-1 significantly repressed MΦ-mediated drug resistance. MΦ had limited protection on PSGL-1-knocked down MM cells. Next, we examined intracellular signal transduction in MM cells, upon interaction with MΦs. Src family kinase and Erk1/2 kinase were activated in MM cells, after coculture with MΦs. Coculture also stimulated PSGL-1 and c-myc overexpression in MM cells. Inhibition of Src family kinase, Erk1/2 kinase, or c-myc by small molecule inhibitors impaired MΦ-mediated MM chemoresistance. The overexpression of PSGL-1, under coculture condition, could be repressed by IFN-α neutralization antibody. More importantly, coculture with MΦ could not stimulate Erk1/2 activation or c-myc overexpression in PSGL-1-knocked down MM cells, suggesting that Erk1/2 and c-myc were downstream of PSGL-1-initiated signal transduction. Finally, we established a NOD-SCID mouse model to test MΦ-mediated MM chemoresistance in vivo. MM tumors with MΦ infiltration grew significantly faster than MM, only, tumors and were more resistant to melphalan treatment. Overall, our data demonstrated a mechanism of MΦ-mediated chemoresistance, both in vitro and in vivo. Based on our findings, MΦ-targeted therapy in MM treatment may be beneficial to improve the effectiveness of MM chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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