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.
Bone marrow monocyte-/macrophage-derived activin A mediates the osteoclastogenic effect of IL-3 in multiple myeloma.
Specimen part, Disease, Disease stage, Treatment
View SamplesIn 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.
Hypoxia-inducible factor (HIF)-1α suppression in myeloma cells blocks tumoral growth in vivo inhibiting angiogenesis and bone destruction.
Specimen part, Cell line
View SamplesGalectin-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.
Galectin-1 suppression delineates a new strategy to inhibit myeloma-induced angiogenesis and tumoral growth in vivo.
Specimen part, Cell line
View SamplesComparison of gene expression profile of E. coli 83972 grown in minimal lab media, in urine and in 3 individual patients.
Global gene expression profiling of the asymptomatic bacteriuria Escherichia coli strain 83972 in the human urinary tract.
None
No sample metadata fields
View SamplesIdentification of genes differentially expressed in roots of Arabidopsis Col-0 and ndr1-1 mutants 48 h post inoculation with the fungal pathogen Verticillium longisporum.
Susceptibility to Verticillium longisporum is linked to monoterpene production by TPS23/27 in Arabidopsis.
Age, Specimen part, Time
View SamplesDetection of single feature polymorphisms comparing five barley genotypes. Gene expression under unstressed and drought stressed conditions.
Detecting single-feature polymorphisms using oligonucleotide arrays and robustified projection pursuit.
No sample metadata fields
View SamplesThe in vitro effect of infection with different strains of Toxoplasma gondii was tested 24 hours after infection of Human Foreskin Fibroblasts (HFF)
Integrative genomic approaches highlight a family of parasite-specific kinases that regulate host responses.
No sample metadata fields
View SamplesWe used microarray to compare global gene expression profiles between 5 GNAQ/11 mutant uveal melanoma cell lines (GNAQ mutant: 92-1, omm1.3, mel270; GNA11 mutant: omm-gn11 and upmd-1) and 5 GNAQ/11 wild type melanoma cell lines(sk-mel-2, mm415, mm485, sk-mel-5 and mum2c). Uveal melanoma is the most common intraocular tumor that mainly metastasizes to the liver in about 50% patients. Over 80% of UMs harbor GNAQ or GNA11 activating mutation. Currently there is no effective treatment available for UM patients. Results provide insights into downstream signaling of oncogenic GNAQ/11 and identification of therapeutic targets in UM.
RasGRP3 Mediates MAPK Pathway Activation in GNAQ Mutant Uveal Melanoma.
No sample metadata fields
View SamplesSingle-neuron transcriptome profiles of Dorsal Raphe neurons marked by a history of expression of Drd2::Cre and Pet1::Flpe (GFP+), as well as Dorsal Raphe neurons marked by a history of Pet1::Flpe expression only (mCherry+). Overall design: GFP and mCherry expressing neurons from triple transgenic Drd2::Cre;Pet1::Flpe;RC:FrePe mice were acutely dissociated, manually sorted, and single-neuron RNA-seq was performed (17 GFP+ cells, 8 mCherry+ cells).
Identification of Serotonergic Neuronal Modules that Affect Aggressive Behavior.
Specimen part, Subject
View SamplesThis SuperSeries is composed of the SubSeries listed below.
Differential induction of TLR3-dependent innate immune signaling by closely related parasite species.
Specimen part, Cell line
View Samples