scholarly journals Hypoxia promotes IL-32 expression in myeloma cells, and high expression is associated with poor survival and bone loss

2017 ◽  
Vol 1 (27) ◽  
pp. 2656-2666 ◽  
Author(s):  
Muhammad Zahoor ◽  
Marita Westhrin ◽  
Kristin Roseth Aass ◽  
Siv Helen Moen ◽  
Kristine Misund ◽  
...  
Keyword(s):  
Bone Loss ◽  
Proinflammatory Cytokine ◽  
Plasma Cells ◽  
Bone Destruction ◽  
High Expression ◽  
Poor Survival ◽  
Myeloma Cells ◽  
Key Points

Key Points IL-32 is a proinflammatory cytokine expressed by plasma cells in a subset of MM patients, and high expression correlates with poor survival. IL-32 is induced by hypoxia and secreted from MM cells in EVs that promote bone destruction.

scholarly journals Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

Blood ◽  
2018 ◽  
Vol 132 (10) ◽  
pp. 1064-1074 ◽  
Author(s):  
Coline Haxaire ◽  
Narine Hakobyan ◽  
Tania Pannellini ◽  
Camila Carballo ◽  
David McIlwain ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Loss ◽  
Proinflammatory Cytokine ◽  
Hemophilic Arthropathy ◽  
Tnf Α ◽  
Key Points

Key Points Blood and its components activated the iRhom2/ADAM17-dependent release of the proinflammatory cytokine TNF-α from macrophages. The iRhom2/ADAM17/TNF-α pathway emerged as a potential new target to prevent bone resorption following a joint bleed in mice.

scholarly journals Chondroitin Synthase 1 Is a Key Molecule in Myeloma Cell-Osteoclast Interactions

2004 ◽  
Vol 280 (16) ◽  
pp. 15666-15672 ◽  
Author(s):  
Larry Yin
Keyword(s):  
Bone Marrow ◽  
Notch Signaling ◽  
Conditioned Medium ◽  
Molecular Mechanisms ◽  
Plasma Cells ◽  
Ex Vivo ◽  
Bone Destruction ◽  
Fold Increase ◽  
Myeloma Cell ◽  
Myeloma Cells

There is a symbiotic relationship between continued growth and proliferation of myeloma cells and the bone destructive process. It has been shown in animal models that blocking bone destruction can result in decreased myeloma tumor burden. Osteoclasts are bone destroying cells found in the bone marrow, and their significance in myeloma is supported by recent findings that osteoclasts alone can support sustained survival and proliferation of purified primary myeloma cells inex vivoco-cultures. However, molecular mechanisms associated with interactions between myeloma cells and osteoclasts remain unclear. Here, we show that when myeloma plasma cells are co-cultured with osteoclasts, chondroitin synthase 1 (CHSY1) is the most significantly altered soluble, secreted protein present in the conditioned medium. RNA interference experiments with CHSY1 small interfering RNA (siRNA) reduced the amount of CHSY1 in the co-culture conditioned medium, and this was associated with a 6.25-fold increase in apoptotic myeloma cells over control co-cultures. CHSY1 contains a Fringe domain, and Fringe is well known for its regulation of Notch signaling via its DDD motif. And interestingly, Fringe domain in CHSY1 has this DDD motif. Shortly after co-culture with osteoclasts, we found that the Notch2 receptor was activated in myeloma cells but Notch1 was not. Activation of Notch2 was down-regulated by CHSY1 siRNA treatment. Modulating Notch signaling by CHSY1 via its DDD motif provides new insight into mechanisms of the interactions between myeloma cells and their bone marrow microenvironment. Targeting this interaction could shed light on treatment of myeloma, which is currently incurable.

Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3002-3007 ◽  
Author(s):  
Therese Standal ◽  
Carina Seidel ◽  
Øyvind Hjertner ◽  
Torben Plesner ◽  
Ralph D. Sanderson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Nuclear Factor Κb ◽  
Heparin Binding ◽  
Bone Homeostasis ◽  
Myeloma Cells ◽  
Heparan Sulfates

Multiple myeloma (MM) is a hematologic malignancy characterized by accumulation of plasma cells in the bone marrow (BM). Bone destruction is a complication of the disease and is usually associated with severe morbidity. The balance between receptor activator of nuclear factor-κB (NF-κB) ligand and osteoprotegerin (OPG) is of major importance in bone homeostasis. We have recently shown that serum OPG levels are lower in patients with myeloma than in healthy individuals. Here we show that myeloma cells can bind, internalize, and degrade OPG, thereby providing a possible explanation for the lower levels of OPG in the BM of patients with MM. This process is dependent on interaction of OPG with heparan sulfates on the myeloma cells. The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered.

scholarly journals Ticagrelor Modulates Proliferation in Multiple Myeloma Via P1 and P2 Receptor-Mediated Mechanisms

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5694-5694
Author(s):  
Elan Meltzer ◽  
Aranzazu Mediero ◽  
Carl Whatling ◽  
Jeffrey S Berger ◽  
Bruce Cronstein
Keyword(s):  
Multiple Myeloma ◽  
Cell Proliferation ◽  
Research Funding ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Bone Destruction ◽  
Extracellular Adenosine ◽  
Myeloma Cells ◽  
Platelet Releasate

Abstract Background:Multiple Myeloma (MM) is a hematologic malignancy involving uncontrolled proliferation of plasma cells and is particularly trophic to bone where it induces osteoclast-mediated bone destruction. Ticagrelor is a platelet inhibitor that blocks P2Y12 receptors and inhibits ENT1-mediated adenosine uptake, thereby increasing extracellular adenosine, which activates P1 receptors. Prior studies demonstrate that ticagrelor increases life span in a murine model of MM via its effect on extracellular adenosine. Prior studies also demonstrate an increase in proliferation, in vitro, and tumor growth, in vivo, of MM cells in the presence of platelet releasate. Ticagrelor blocks in vitro platelet-stimulated myeloma proliferation, suggesting a positive relationship and interaction between active platelets and multiple myeloma. We therefore determined whether the effect of ticagrelor on myeloma cells was mediated by extra-cellular adenosine or/and inhibition of platelet function. Methods:Human primary myeloma cells (KMS) were incubated with ticagrelor (10-9-10-4 M) in the presence of 5ng/ml IL-6 in the absence/presence of an A2AR antagonist (ZM241385 10-6M) and platelets (1:500 myeloma cell:platelets). In other experiments MM cells were incubated in the presence of platelet releasate, releasate from platelets treated with ticagrelor, or ticagrelor alone. Proliferation was assayed by Cell Titer MTS assay (Promega). Results: Ticagrelor inhibited MM cell proliferation by 20% (p<0.0001, IC50=0.5µM). This effect was abrogated by ZM241385 (48±6% increased vs. ticagrelor, p<0.0001). Platelet releasate increased MM proliferation by 33±6% (p<0.05) and ticagrelor inhibited the effect of platelet releasate on MM cell proliferation (IC50=0.12µM). Conclusions:These results suggest that ticagrelor inhibits proliferation of malignant plasma cells by a mechanism dependent on both adenosine A2A and platelet P2Y12 receptors. Moreover, platelet releasate intensifies proliferation, and this effect is reversed when the P2Y12 receptor is blocked by ticagrelor. Figure 1 Figure 1. Figure 2 Figure 2. Figure 3 Figure 3. Disclosures Meltzer: NIH: Research Funding; Celgene: Research Funding; AstraZeneca: Research Funding. Mediero:AstraZeneca: Research Funding; Celgene: Research Funding; NIH: Research Funding. Whatling:AstraZeneca: Employment. Berger:Merck: Membership on an entity's Board of Directors or advisory committees; AZ: Research Funding. Cronstein:AstraZeneca: Consultancy, Research Funding; CanFite: Equity Ownership; Gizmo Therapeutics: Consultancy; Eli Lilly & Co.: Consultancy; NIH: Research Funding; Celgene: Research Funding.

Bortezomib Protects Osteoblasts from Glucocorticoid-Induced Damage, and Enhances Glucocorticoid-Induced Toxicity Against Osteoclasts and Myeloma Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3523-3523
Author(s):  
Kent Soe ◽  
Thomas L. Andersen ◽  
Katarzyna Kupisiewicz ◽  
Torben Plesner ◽  
Jean-Marie Delaisse
Keyword(s):  
Multiple Myeloma ◽  
Bone Repair ◽  
Plasma Cells ◽  
Bone Cells ◽  
Negative Impact ◽  
Bone Destruction ◽  
Myeloma Cells ◽  
The Impact ◽  
Human Osteoclasts

Abstract Introduction: Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow, and leads most often to bone destruction by osteoclasts and prevention of bone repair by osteoblasts. Bortezomib and glucocorticoids are both powerful anti-myeloma drugs that are used for killing malignant plasma cells in the patients. Furthermore bortezomib has direct anti-osteoclastic and pro-osteoblastic properties that may contribute to bone protection in multiple myeloma, while glucocorticoids have more ambiguous effects on these bone cells and are clearly anti-osteoblastic. Recent clinical trials based on the combination of bortezomib and glucocorticoids drew the attention on the very promising anti-myeloma efficiency of this combination. However, the bone cell response of this combination has not been tested. In order to address this question, we performed an in vitro study, and importantly adapted our in vitro model to mimic the pharmacokinetics of bortezomib and glucocorticoid in the patients. Methods: Myeloma cell lines, primary human osteoclasts and osteoblast-like cells (MC3T3) were pulse-treated or not with clinically relevant doses of bortezomib (12.5, 25 or 50 nM) for 3 hours. Subsequently, the cells were exposed during a 3-day culture to 1.6 μM prednisolone which approximately corresponds to a dose of 50 mg prednisolone in a patient. The impact of the treatment on the cells was determined by survival, activity and gene expression. Results: Bortezomib as a single treatment was very efficient in killing sensitive myeloma cells (OPM2) whereas the more resistant cells (U266) were more efficiently killed in combination with prednisolone. The release of TRAP from primary human osteoclasts, a marker of osteoclastic activation, was strongly inhibited by bortezomib treatment alone, but only in combination with prednisolone did it result in killing of osteoclasts. Survival of osteoblast like cells was uninfluenced by treatment with bortezomib alone. In contrast, as shown previously, prednisolone strongly reduced osteoblast survival. Most importantly however, a 3 hr pre-treatment with bortezomib protected the osteoblasts against the detrimental effects of glucocorticoids. Ongoing investigations by Q-PCR indicate that important markers of osteoblast maturation remain high if the osteoblasts were pre-treated with bortezomib prior to prednisolone exposure. Conclusion: Our study demonstrates in conditions relevant to treatment of myeloma patients, that combining bortezomib and glucocorticoids has a direct synergistic effect against myeloma cells and osteoclasts, and that bortezomib protects directly osteoblasts from the negative impact of glucocorticoids. Thus, the combination of bortezomib and glucocorticoids is not only a powerful treatment of multiple myeloma itself, but also shows promise for treating myeloma bone disease.

scholarly journals Dependence on glutamine uptake and glutamine addiction characterize myeloma cells: a new attractive target

Blood ◽  
2016 ◽  
Vol 128 (5) ◽  
pp. 667-679 ◽  
Author(s):  
Marina Bolzoni ◽  
Martina Chiu ◽  
Fabrizio Accardi ◽  
Rosanna Vescovini ◽  
Irma Airoldi ◽  
...  
Keyword(s):  
Glutamine Synthetase ◽  
High Expression ◽  
Myeloma Cells ◽  
Key Points ◽  
Glutamine Transporters ◽  
Glutamine Uptake

Key Points Myeloma cells produce ammonium in the presence of glutamine, showing high glutaminase and low glutamine synthetase expression. Myeloma cells show high expression of glutamine transporters and inhibition of ASCT2 transporter hinders myeloma growth.

Bone disease as the first manifestation of systemic AL-amyloidosis

2020 ◽  
Vol 92 (7) ◽  
pp. 85-89
Author(s):  
L. P. Mendeleeva ◽  
I. G. Rekhtina ◽  
A. M. Kovrigina ◽  
I. E. Kostina ◽  
V. A. Khyshova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Bone Disease ◽  
Plasma Cells ◽  
Interventricular Septum ◽  
Bone Destruction ◽  
Amyloid Deposition ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Linear Type

Our case demonstrates severe bone disease in primary AL-amyloidosis without concomitant multiple myeloma. A 30-year-old man had spontaneous vertebral fracture Th8. A computed tomography scan suggested multiple foci of lesions in all the bones. In bone marrow and resected rib werent detected any tumor cells. After 15 years from the beginning of the disease, nephrotic syndrome developed. Based on the kidney biopsy, AL-amyloidosis was confirmed. Amyloid was also detected in the bowel and bone marrow. On the indirect signs (thickening of the interventricular septum 16 mm and increased NT-proBNP 2200 pg/ml), a cardial involvement was confirmed. In the bone marrow (from three sites) was found 2.85% clonal plasma cells with immunophenotype СD138+, СD38dim, СD19-, СD117+, СD81-, СD27-, СD56-. FISH method revealed polysomy 5,9,15 in 3% of the nuclei. Serum free light chain Kappa 575 mg/l (/44.9) was detected. Multiple foci of destruction with increased metabolic activity (SUVmax 3.6) were visualized on PET-CT, and an surgical intervention biopsy was performed from two foci. The number of plasma cells from the destruction foci was 2.5%, and massive amyloid deposition was detected. On CT scan foci of lesions differed from bone lesions at multiple myeloma. Bone fragments of point and linear type (button sequestration) were visualized in most of the destruction foci. The content of the lesion was low density. There was no extraossal spread from large zones of destruction. There was also spontaneous scarring of the some lesions (without therapy). Thus, the diagnosis of multiple myeloma was excluded on the basis based on x-ray signs, of the duration of osteodestructive syndrome (15 years), the absence of plasma infiltration in the bone marrow, including from foci of bone destruction by open biopsy. This observation proves the possibility of damage to the skeleton due to amyloid deposition and justifies the need to include AL-amyloidosis in the spectrum of differential diagnosis of diseases that occur with osteodestructive syndrome.

scholarly journals Hypoxia-induced CREB cooperates MMSET to modify chromatin and promote DKK1 expression in multiple myeloma

Oncogene ◽  
2021 ◽  
Author(s):  
Yinyin Xu ◽  
Jing Guo ◽  
Jing Liu ◽  
Ying Xie ◽  
Xin Li ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Combined Treatment ◽  
Hypoxia Inducible Factor ◽  
Bone Destruction ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Downstream Target ◽  
Dkk1 Expression

AbstractMyeloma cells produce excessive levels of dickkopf-1 (DKK1), which mediates the inhibition of Wnt signaling in osteoblasts, leading to multiple myeloma (MM) bone disease. Nevertheless, the precise mechanisms underlying DKK1 overexpression in myeloma remain incompletely understood. Herein, we provide evidence that hypoxia promotes DKK1 expression in myeloma cells. Under hypoxic conditions, p38 kinase phosphorylated cAMP-responsive element-binding protein (CREB) and drove its nuclear import to activate DKK1 transcription. In addition, high levels of DKK1 were associated with the presence of focal bone lesions in patients with t(4;14) MM, overexpressing the histone methyltransferase MMSET, which was identified as a downstream target gene of hypoxia-inducible factor (HIF)-1α. Furthermore, we found that CREB could recruit MMSET, leading to the stabilization of HIF-1α protein and the increased dimethylation of histone H3 at lysine 36 on the DKK1 promoter. Knockdown of CREB in myeloma cells alleviated the suppression of osteoblastogenesis by myeloma-secreted DKK1 in vitro. Combined treatment with a CREB inhibitor and the hypoxia-activated prodrug TH-302 (evofosfamide) significantly reduced MM-induced bone destruction in vivo. Taken together, our findings reveal that hypoxia and a cytogenetic abnormality regulate DKK1 expression in myeloma cells, and provide an additional rationale for the development of therapeutic strategies that interrupt DKK1 to cure MM.

Genome-Wide Transcriptome Analysis Identifies Molecular Patterns of FDG-PET/CT Biomarkers in MM Patients from the Cassiopet Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 26-26
Author(s):  
Jean-Baptiste Alberge ◽  
Bastien Jamet ◽  
Clement Bailly ◽  
Cyrille Touzeau ◽  
Jonathan Cruard ◽  
...  
Keyword(s):  
High Risk ◽  
Fdg Pet ◽  
Research Funding ◽  
Plasma Cells ◽  
High Expression ◽  
Imaging Biomarkers ◽  
Rna Seq ◽  
Molecular Subgroups ◽  
Pet Ct ◽  
Fdg Pet Ct

Background Positron emission tomography (PET) using 18Fluorodeoxyglucose (FDG) provides independent prognostic informations in newly diagnosed multiple myeloma (NDMM) patients (Moreau et al, ASH 2019; Moreau et al, JCO 2017; Zamagni et al, Blood 2011). At baseline, FDG-PET/CT characteristics such as maximum standardized uptake value (SUVmax), presence of extramedullary disease (EMD), and paramedullary disease (PMD) define high-risk NDMM patients. Similarly, the presence of negative FDG-PET/CT at baseline has been associated with favorable outcome in NDMM patients (Abe et al, EJNMMI 2019; Moreau et al, ASH 2019). The aim of the present study was to identify MM molecular features associated with these functional imaging biomarkers. Methods A group of 136 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov, number NCT02541383) were subjected to whole genome expression profiling using RNA sequencing (RNA-seq) on sorted bone marrow plasma cells in addition to FDG-PET/CT imaging at baseline. RNA-seq reads were aligned to hg38 reference genome with STAR and subjected to differential expression testing with DESeq2 with sample purity treated as a model covariate. High risk group with the GEP70 signature and classification from the seven molecular subgroups (CD-1, CD-2, HY, LB, MF, MS, and PR) were determined by weighted mean value of gene expression (Zhan et al, Blood 2006). Special attention was paid to genes associated with glucose metabolism and related to plasma cells proliferation. On FDG-PET/CT, SUVmax of areas of focally increased tracer uptake on bone was determined and the presence of EMD or PMD identified. Results FDG-PET/CT was positive in 108 patients out of 136 (79,4%), with 19 (14%) and 15 (11%) of them presenting PMD and EMD disease respectively. Expression level of glucose transporter GLUT1 was independent of these three imaging biomarkers (FDG-PET/CT positivity, EMD and PMD), while HK2 was downregulated in negative scans only (Fold Change = 2.1, padj=0.02). GLUT5 expression was associated with positive FDG-PET/CT (Fold Change = 3.5, padj = 8E-4). Both GLUT1 and HK2 weakly correlated with SUVmax (r=0.26 and 0.36, respectively). Of note, negative FDG-PET/CT were enriched for the LB group of patients, consistent with the lower incidence of MRI-defined bone lesions reported in this subgroup, and it remained independent of the GEP70 signature. Furthermore, high risk GEP70 signature was associated with a SUVmax ≥ 4, and correlated with the presence of PMD (OR=3.2, CI=[0.95-10.6], p=0.03), but not with EMD (p=0.7).Conversely, there was no patient from the LB group with detected PMD on imaging, but 25% (2/8) showed EMD, suggesting that different biological features support both disease patterns. Finally, positive PET/CT profiles seemed to display two distinct signatures with either high expression of proliferation genes (MKI67, PCNA, TOP2A, STMN1), or high expression of GLUT5 and lymphocyte antigens (CD19, CD30L, and CCR2), suggesting a different phenotype for this subgroup. This finding was independent of a high SUVmax. Conclusion Our study confirmed that negative FDG-PET/CT at baseline is associated with low HK2 expression while positive exams showed increased GLUT5 expression and proliferation markers. We describe a strong correlation between two imaging biomarkers (baseline SUVmax and PMD) and high risk signature and molecular subgroup with highly proliferative disease. On the contrary, EMD appeared independent of high risk signature or molecular subgroups. Additional studies will confirm and extend the correlation between imaging and clinical features of the disease and molecular characteristics of malignant plasma cells. Disclosures Touzeau: Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Moreau:Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria.

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