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GSE37302
Homo sapiens
9 Downloadable Samples
Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Multiple myeloma (MM)-induced osteoclast (OC) formation occurs in close contact with MM cell infiltration into the bone marrow (BM) due to the imbalance of the receptor activator of NF-kappa-B ligand (RANKL)/osteoprotegerin (OPG) ratio in favor of RANKL in the micorenvironment. Soluble factors including CCL3/MIP-1?, IL7 and IL-3 also contribute to the increased OC formation in MM.The immunomodulatory drugs (IMiDs) directly inhibit OCs, however their effect on the mechanisms involved in MM-induced OC formation are not known and have been investigated in this study. We found that both Lenalidomide (LEN) and Pomalidomide (POM), at concentration ranging reached in vivo, significantly blunted RANKL up-regulation normalizing the RANKL/OPG ratio in human BM osteoprogenitor cells (PreOBs) co-cultured with MM cells and inhibited CCL3/MIP-1? production by MM cells. The reduction of CD49d expression on MM cells, a molecule critically involved in RANKL up-regulation in the micorenvironment, accompanied this effect. Consistently the pro-osteoclastogenic property of the conditioned medium of MM cells co-cultured with PreOBs was reduced in the presence of both IMiDs. By microarray analysis we further investigated the effect of POM and LEN on the transcriptional profile of both MM cells and PreOBs. We found a significant down-regulation in MM cells, in addition to CD49d, of genes belonging to the adhesion molecules family such as ITGA8 and ICAM2 (CD102) induced by both IMiDs compounds. In conclusion our data suggest that POM and LEN inhibits MM-induced OC formation through the inhibition of RANKL/OPG ratio targeting the expression of adhesion molecules by MM cells.
Publication Title
Immunomodulatory drugs lenalidomide and pomalidomide inhibit multiple myeloma-induced osteoclast formation and the RANKL/OPG ratio in the myeloma microenvironment targeting the expression of adhesion molecules.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Myeloma bone disease is characterized by tremendous bone destruction with suppressed bone formation. IL-3 is a multifunctional cytokine that increases myeloma cell growth and osteoclast proliferation while inhibiting osteoblast differentiation. While IL-3 appears to be an attractive therapeutic target for myeloma, attempts at targeting IL-3 have been unsuccessful due to IL-3s effects on normal hematopoiesis. Thus identification of IL-3s downstream effects in MMBD is important for effective targeting of this cytokine in MM. Here we demonstrated that treatment of myeloma patient CD14+ bone marrow monocyte / macrophages with IL-3 induces high levels of Activin A (ActA), a pluripotent TGF- superfamily member that, like IL-3, modulates MMBD by enhancing osteoclastogenesis and inhibiting osteoblasts. We show that IL-3 induced osteoclastogenesis is mediated by ActA and is RANKL independent. Additionally, IL-3 induced ActA secretion is greatest early in osteoclastogenesis and ActA acts early in osteoclastogenesis. Therefore we suggest that therapies targeting ActA production should block IL-3s effects in myeloma bone disease.
Publication Title
Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma.
Sample Metadata Fields
Specimen part, Disease, Disease stage, Treatment
View Samples- Homo sapiens
- 5 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
The involvement of osteocytes in multiple myeloma (MM)-induced osteoclast formation and the occurrence of bone lesions are still unknown. Osteocytes regulate bone remodeling at least in part through the cell death and apoptosis triggering osteoclast recruitment and formation. In this study, firstly we shown that MM cells increased osteocyte death and affect their transcriptional profile evaluated by microarray analysis up-regulating osteoclastogenic cytokines as interleukin (IL)-11. Consistently we show that the conditioned media of human pre-osteocytes co-cultured with MM cells significantly increased osteoclastogenesis. To translate into a clinical perspective such in vitro evidences, we then performed histological analysis on bone biopsies obtained from MM patients, MGUS and healthy controls. We found a significant reduction in the number of viable osteocytes in MM patients as compared to controls. A significant negative correlation between the number of viable osteocytes and that of osteoclasts was also demonstrated. Moreover, as regards the skeletal involvement, we found that MM patients with bone lesions have a significant lower number of viable osteocyte than those without. Overall, our data suggest a role of osteocytic cell death in MM-induced osteoclast formation in vitro and MM bone disease in vivo in MM patients.
Publication Title
Increased osteocyte death in multiple myeloma patients: role in myeloma-induced osteoclast formation.
Sample Metadata Fields
Specimen part, Cell line, Treatment
View Samples- Homo sapiens
- 2 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
A rare complication of multiple myeloma is a secondary extramedullary involvement, and the skin is one of the possible sites, due to the physiological homing of plasma cells (PCs) into the skin. The article reports a case of a relapsed refractory MM patient, who developed a cutaneous localization after 16 months from the diagnosis under Bortezomib treatment without a leukemic phase. Patient was refractory to Bortezomib. We analyzed the gene expression profiles, the immunophenotypic and immunohistochemistry profiles of MM cells across the course of the disease at the bone marrow and skin localization. Data obtained were further expanded by an immunohistochemistry analysis on selected molecules in a large cohort of MM patients with cutaneous localization. In particular we focused on the expression of chemokines and chemokine receptors involved in the PC skin homing.
Publication Title
Cutaneous localization in multiple myeloma in the context of bortezomib-based treatment: how do myeloma cells escape from the bone marrow to the skin?
Sample Metadata Fields
Sex, Age, Specimen part, Subject, Time
View Samples- Escherichia coli
- 6 Downloadable Samples
- Affymetrix E. coli Genome 2.0 Array (ecoli2)
Description
Small RNAs (sRNA) that act by base pairing with trans-encoded mRNAs modulate metabolism in response to a variety of environmental stimuli. Here, we describe an Hfq-binding sRNA (FnrS) whose expression is induced upon a shift from aerobic to anaerobic conditions and which acts to down regulate the levels of a variety of mRNAs encoding metabolic enzymes. Anaerobic induction in minimal medium depends strongly on FNR but is also affected by ArcA and CRP. Whole genome expression analysis showed that the levels of at least 32 mRNAs are down regulated upon FnrS overexpression, 15 of which are predicted to base pair with FnrS by TargetRNA. The sRNA is highly conserved across its entire length in numerous enterobacteria, and mutation analysis revealed that two separate regions of FnrS base pair with different sets of target mRNAs. The majority of the target genes previously reported to be down regulated in an FNR-dependent manner lack recognizable FNR binding sites. We thus suggest that FnrS extends the FNR regulon and increases the efficiency of anaerobic metabolism by repressing the synthesis of enzymes that are not needed under these conditions.
Publication Title
Reprogramming of anaerobic metabolism by the FnrS small RNA.
Sample Metadata Fields
No sample metadata fields
View Samples- Escherichia coli str. k-12 substr. mg1655
- 6 Downloadable Samples
- Affymetrix E. coli Genome 2.0 Array (ecoli2)
Description
Bacteria selectively consume some carbon sources over others through a regulatory mechanism termed catabolite repression. Here, we show that the base pairing RNA Spot 42 plays a broad role in catabolite repression in Escherichia coli by directly repressing genes involved in central and secondary metabolism, redox balancing, and the consumption of diverse non-preferred carbon sources. Many of the genes repressed by Spot 42 are transcriptionally activated by the global regulator CRP. Since CRP represses Spot 42, these regulators participate in a specific regulatory circuit called a multi-output feedforward loop. We found that this loop can reduce leaky expression of target genes in the presence of glucose and can maintain repression of target genes under changing nutrient conditions. Our results suggest that base pairing RNAs in feedforward loops can help shape the steady-state levels and dynamics of gene expression.
Publication Title
The base-pairing RNA spot 42 participates in a multioutput feedforward loop to help enact catabolite repression in Escherichia coli.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 4 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
In multiple myeloma (MM), hypoxia-inducible transcription factor-1 (HIF-1) is overexpressed in the MM cells of the hypoxic bone marrow (BM) microenvironment. Herein, we explored in MM cells the in vitro and in vivo effects of persistent HIF-1 inhibition by expression of a lentivirus shRNA pool on proliferation, survival and transcriptional and pro-angiogenic profiles. Among the significantly modulated genes (326 and 361 genes in hypoxic and normoxic condition, respectively), we found that HIF-1 inhibition in the human myeloma cell line JJN3 downregulates the pro-angiogenic molecules VEGF, IL8, IL10, CCL2, CCL5, and MMP9. Interestingly, several pro-osteoclastogenic cytokines were also inhibited, such as IL-7 and CCL3/MIP-1. The effect of HIF-1 inhibition was assessed in vivo in NOD/SCID mice both in subcutaneous and intratibial models, indicating in either case a dramatic reduction of weight and volume of the tumor burden as a consequence of HIF-1 knockdown. Moreover, a significant reduction of the number of vessels per field and VEGF immunostaining were observed. Finally, in the intra-tibial experiments, HIF-1 inhibition significantly blocks JJN3-induced bone destruction. Overall, our data indicate that HIF-1 suppression in MM cells significantly blocks MM-induced angiogenesis and reduces both tumor burden and bone destruction in vivo, strongly indicating HIF-1 as an emerging therapeutic target in MM.
Publication Title
Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 47 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Bone marrow monocytes are primarily committed to osteoclast formation. It is, however, unknown whether potential primary alterations are specifically present in bone marrow monocytes from patients with multiple myeloma, smoldering myeloma or monoclonal gammopathy of undetermined significance. We analyzed the immunophenotypic and transcriptional profiles of bone marrow CD14+ monocytes in a cohort of patients with different types of monoclonal gammopathies to identify alterations involved in myeloma-enhanced osteoclastogenesis. The number of bone marrow CD14+CD16+ cells was higher in patients with active myeloma than in those with smoldering myeloma or monoclonal gammopathy of undetermined significance. Interestingly, sorted bone marrow CD14+CD16+ cells from myeloma patients were more pro-osteoclastogenic than CD14+CD16-cells in cultures ex vivo Moreover, transcriptional analysis demonstrated that bone marrow CD14+ cells from patients with multiple myeloma (but neither monoclonal gammopathy of undetermined significance nor smoldering myeloma) significantly upregulated genes involved in osteoclast formation, including IL21RIL21R mRNA over-expression by bone marrow CD14+ cells was independent of the presence of interleukin-21. Consistently, interleukin-21 production by T cells as well as levels of interleukin-21 in the bone marrow were not significantly different among monoclonal gammopathies. Thereafter, we showed that IL21R over-expression in CD14+ cells increased osteoclast formation. Consistently, interleukin-21 receptor signaling inhibition by Janex 1 suppressed osteoclast differentiation from bone marrow CD14+ cells of myeloma patients. Our results indicate that bone marrow monocytes from multiple myeloma patients show distinct features compared to those from patients with indolent monoclonal gammopathies, supporting the role of IL21R over-expression by bone marrow CD14+ cells in enhanced osteoclast formation.
Publication Title
<i>IL21R</i> expressing CD14<sup>+</sup>CD16<sup>+</sup> monocytes expand in multiple myeloma patients leading to increased osteoclasts.
Sample Metadata Fields
Age, Specimen part
View Samples- Escherichia coli str. k-12 substr. mg1655
- 4 Downloadable Samples
- Affymetrix E. coli Genome 2.0 Array (ecoli2)
Description
Escherichia coli possesses >65 small proteins of <50 amino acids, many of which are uncharacterized. We have identified a new small protein, MntS, involved in manganese homeostasis. Manganese is a critical micronutrient, serving as an enzyme cofactor and protecting against oxidative stress. Yet manganese is toxic in excess and little is known about its function in cells. Bacteria carefully control intracellular manganese levels using the transcription regulator MntR. Before this work, mntH, which encodes a manganese importer, was the only gene known to respond to manganese via MntR repression in E. coli K12. We demonstrated that mntS is another member of the MntR manganese regulon. We also identified yebN, which encodes a putative manganese efflux pump, as the first gene positively regulated by MntR in Enterobacteria. Since MntS is expressed when manganese levels are low, causes manganese sensitivity when overexpressed, and binds manganese, we propose that MntS may be a manganese chaperone. This study reveals new factors involved in manganese regulation and metabolism and expands our knowledge of how small proteins function.
Publication Title
The Escherichia coli MntR miniregulon includes genes encoding a small protein and an efflux pump required for manganese homeostasis.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Genome U133 Plus 2.0 Array (hgu133plus2)
Description
Galectin-1 (Gal-1) is a lectin, involved in several processes related to cancer, including immunosuppression, angiogenesis, hypoxia, and metastases. Actually, the Gal-1 expression profile in multiple myeloma (MM) and its pathophysiological role in MMinduced angiogenesis and tumoral growth is unknown. Firstly, we found that Gal-1 was expressed by malignant plasma cells in MM patients and that its expression was up-regulated upon hypoxic treatment (1% of O2). Moreover the stable knock-down of Hypoxia Inducible Factor-1 (HIF-1) in MM cells significantly downregulated Gal-1 expression. Thereafter, we performed Gal-1 inhibition by lentivirus shRNA anti-Gal-1 in human myeloma cell lines (HMCLs) showing that its suppression did not affect cell proliferation and survival but modified their transcriptional profiles either in hypoxia or hypoxia condition. Interestingly pro-angiogenic genes including MMP9 and CCL2 were downregulated and those anti-angiogenic SEMA3A and CXCL10 were up-regulated by Gal-1 inhibition in MM cells. Data were also validated by Real time PCR and at protein level. Consistently we found that Gal-1 suppression in MM cells significantly decreased their pro-angiogenic proprieties by an in vitro assay. These evidences were confirmed in mice injected either subcutaneously or intratibially with HMCLs carrying a stable infection with shRNA anti-inhibition of Gal-1 or with the control vector cell line. Gal-1 suppression in both models showed a significant reduction in the tumoral burden and microvascular density compared to the control mice. Moreover, Gal-1 suppression induced smaller lytic lesions on x-ray in the intratibially model. Overall, our data indicate that Gal-1 is a new potential therapeutic target in MM.
Publication Title
Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.
Sample Metadata Fields
Specimen part, Cell line
View Samples