The Y-box Binding Protein YB-1 Is Associated with Progressive Disease and Mediates Survival and Drug Resistance in Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3385-3385
Author(s):  
Manik Chatterjee ◽  
Christoph Ransco ◽  
Thorsten Stühmer ◽  
Niels Eckstein ◽  
Hans-Dieter Royer ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Cell Lines ◽  
Plasma Cells ◽  
Apoptotic Cell ◽  
Binding Protein ◽  
Regulation Of Transcription ◽  
Drug Induced ◽  
Bone Marrow Biopsies

Abstract Introduction: The Y-box binding protein YB-1 is a member of the cold shock domain protein superfamily and represents one of the most evolutionary conserved nucleic-acid binding proteins. Yb-1 is involved in a wide variety of cellular functions, such as regulation of transcription and translation, but also in DNA-repair and stress response to extracellular signals. Furthermore, recent reports from our group could show that overexpressed YB-1 plays a role in drug resistance of breast cancer cells and might act as an oncogene. The goal of this study was to investigate a potential pathogenetic role of YB-1 in MM. Material and Methods: For the detection of YB-1 expression in vivo, bone marrow biopsies of MM patients were analyzed by immunohistochemistry. The expression of YB-1 protein in a number of MM cell lines was analyzed by Western Blotting. The regulation of YB-1 expression through major signaling pathways, e.g. IL-6R/STAT3, Ras/MAPK and PI3K/AKT, was analyzed using specific inhibitors of these pathways (Sant7, PD98059 and Ly294002). To determine the role of YB-1 for survival and proliferation, siRNA technology was exploited to transiently knockdown the expression of YB-1 in the MM cell lines INA-6 and MM.1s. In addition, these YB-1 knockdown cells were exposed to doxorubicin and melphalan to evaluate the influence of YB-1 on drug resistance. Results: Immunohistochemical analyses of bone marrow biopsies revealed that YB-1 is strongly expressed only in MM cells of samples that show a highly proliferative phenotype. This subgroup of MM patients was characterized by an aggressive clinical course. In contrast, MM cells of samples with a slow proliferative status did not show YB-1 expression. Interestingly, tumor cells of patients that responded to chemotherapy did not express YB-1. Furthermore, neither normal bone marrow plasma cells nor premalignant plasma cells of MGUS patients showed YB-1 expression. YB-1 was detected in all of the evaluated MM cell lines. YB-1 expression was not regulated by the IL-6R/STAT3, Ras/MAPK and PI3K/AKT pathways. Knockdown of YB-1 in INA-6 and MM1.s cells by siRNA resulted in a slow proliferation phenotype with a higher apoptotic cell fraction. In addition, we observed that YB-1 knockdown remarkably sensitized cells towards drug-induced apoptosis. Conclusions: YB-1 expression in MM appears to be correlated with a highly proliferative phenotype and with disease progression. YB-1 contributes to the malignant growth and drug resistance and might be therefore an attractive therapeutical target to circumvent aquired drug resistance in MM.

Genome Wide DNA Methylation Profiling In Patients with Multiple Myeloma.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3622-3622
Author(s):  
Yang Liu ◽  
Shenghua Duan ◽  
Xavier Leleu ◽  
Yong Zhang ◽  
Abdel Kareem A. Azab ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
Cell Lines ◽  
Promoter Region ◽  
Genomic Dna ◽  
Research Funding ◽  
Plasma Cells ◽  
Genome Wide

Abstract Abstract 3622 Introduction: Epigenetic factors such as DNA methylation have been shown to play a crucial role in the pathogenesis and progression of multiple myeloma (MM), yet studies of DNA methylation in MM are still limited. Therefore, in order to better understand the role of DNA methylation and identify specific genes that may be affected by differential methylation in MM patients, we conducted genome-wide DNA methylation profiling in cd138+ plasma cells purified from bone marrow of the patients with MM and normal donors. Methods: Genomic DNA of CD138+ Plasma cell selected from both MM patients and normal primary bone marrow was extracted using QIAGEN genome isolation kit. Following extraction, methylated DNA was isolated by Chip and hybridized to Affymetrix Human 2.0 tiling arrays. Chip assay and array hybridization was performed by Genepathway Inc. CEL files were processed and normalized using the MAT program, and methylation peaks were called from the resulting MAT scores using a custom segmentation method. Peak annotation and characterization of different genomic regions was done with custom tools and using genome annotation files from the UCSC genome database. All peaks were visualized by IGB online software. Medip-PCR was done in human MM cell lines to validate the methylation status. Methylated gene expression was determined by both Semi-quantitative PCR and real-time PCR. 5′aza was used for demethylation in human MM cell lines. Methylated gene expression with or without 5′aza treatment was determined by both Semi-quantitative PCR and real-time PCR. Results: Genomic DNA from CD138+ plasma cells from bone marrow of MM patients showed a significant increase in methylation levels compared to normal controls. We demonstrated that the hypermethylated sites were distributed across the genome in the following proportions: 3.2% in the promoter region; 45.6% in the intragenic region; 5.4 % in the 3′ end region; and 46.8 % in the intergenic region. Furthermore, around 9 % promoter CpG islands (CGIs); 11% intragenic CGIs; 15 % CGIs in 3′end region; and 14.3 % intergenic CGIs of patients genomic DNA were methylated. Moreover 2.1% promoter CGIs; 2.3 % intragenic CGIs; 2.5% CGIs in 3′end region; and 4.7% intergenic CGIs were methylated for the normal control. Medip-PCR showed that the identified methylation pattern in MM patients showed similar results in MM cell lines. Expectedly, we also observed that suppressor of cytokine signaling 1 (SOCS1) was hypermethylated at the promoter region (MAT score=19.986) as has been reported in human cell lines. Importantly, another member of SOCS family SOCS3 showed much stronger signal in the promoter region with CpG island (MAT score=31.707) in MM patients compared to normal control. Notably, the expression of two members of TNFR superfamily TNFRSF18 and TNFRSF4 which play an important role in development and programmed cell death of lymphocyte significantly have increased 283 and 141-fold after treatment with 5′aza in MM cell lines. Conclusion: These findings enhance our understanding of the role of DNA methylation in MM, as one of the epigenetic changes that may contribute to the pathogenesis of this disease. The identification and functional characterization of novel key molecules affected by DNA methylation will provide deeper insight into the molecular basis of MM disease. Disclosures: Leleu: Celgene: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; Leo Pharma: Consultancy; Amgen: Consultancy; Chugai: Research Funding; Roche: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Anderson:Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Stroma cells and Monocytes make Multiple Myeloma Cells Active In Bone Marrow Microenviroment

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5333-5333
Author(s):  
Hiroshi Ikeda ◽  
Tadao Ishida ◽  
Toshiaki Hayashi ◽  
Yuka Aoki ◽  
Yasuhisa Shinomura
Keyword(s):  
Stem Cells ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
Cell Contact ◽  
Drug Induced ◽  
Myeloma Cells

Abstract The Bone marrow (BM) microenvironment plays crucial role in pathogenesis of multiple myeloma　(MM). Paracrine secretion of cytokines in BM stromal cells promotes multiple myeloma cell proliferation and protects against drug-induced cytotoxicity. In current study, monocytes, component of BM cells, can directly promote mesenchymal stem cells osteogenic differentiation through cell contact interactions. Down-regulation of inhibitors such as DKK1 drives the differentiation of mesechymal stem cells into osteoblasts. In this study, we examined the role of monocytes as a potential niche component that supports myeloma cells. We investigated the proliferation of MM cell lines cultured alone or co-cultured with BM stromal cells, monocytes, or a combination of BM stromal cells and monocytes. Consistently, we observed increased proliferation of MM cell lines in the presence of either BM stromal cells or monocytes compared to cell line-only control. Furthermore, the co-culture of BM stromal cells plus monocytes induced the greatest degree of proliferation of myeloma cells. In addition to increased proliferation, BMSCs and monocytes decreased the rate of apoptosis of myeloma cells. Our results therefore suggest that highlights the role of monocyte as an important component of the BM microenvironment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Is There Any Relationship between Human Herpesvirus-8 and Multiple Myeloma?

Lymphoma ◽  
2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Mohammad Hadi Sadeghian ◽  
Maryam Mohammadnia Avval ◽  
Hossein Ayatollahi ◽  
Mohammad Reza Keramati ◽  
Bahram Memar ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Human Herpesvirus ◽  
The Body ◽  
Human Herpesvirus 8 ◽  
Bone Marrow Biopsies ◽  
Exact Test ◽  
Herpesvirus 8

Background. Human herpesvirus-8 (HHV-8) is associated with some human diseases including Kaposi’s sarcoma and also some B-cell lymphoproliferative disorders. Few studies have highlighted the potential role of HHV-8 in the development of multiple myeloma (MM) which is known as a malignant proliferation of plasma cells derived from a single clone. Aims. The aim of this study was to find a relationship between HHV-8 and MM using polymerase chain reaction (PCR) method. Materials and Methods. This study was conducted on 30 formalin-fixed, paraffin-embedded (FFPE) bone marrow biopsies of multiple myeloma and 30 normal FFPE bone marrow biopsies. After the sample preparation, Deoxyribonucleic acid (DNA) was extracted by nonheating procedure. PCR for HHV-8 virus was carried out with commercial kit and the PCR products were visualized by gel electrophoresis. Finally, the statistical analysis was performed. Results. HHV-8 virus was not detected by PCR from FFPE blocks of multiple myeloma samples, while only one of the controls showed DNA band of the corrected molecular weights. Fisher’s exact test showed that no statistical differences were found between the two groups (P=0.999). Conclusion. Our report adds to the body of evidence that there is no association between HHV- 8 and MM against a major role of HHV-8 infection in the pathogenesis of clonal plasma cell proliferation.

scholarly journals Characterization of a monoclonal antibody having selective reactivity with normal and neoplastic plasma cells

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 238-245 ◽  
Author(s):  
AW Tong ◽  
JC Lee ◽  
MJ Stone
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Pokeweed Mitogen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunoperoxidase Technique ◽  
Binding Studies ◽  
Bone Marrow Biopsies

A myeloma cell-reactive monoclonal antibody (MoAb), MM4, was generated from BALB/c mice immunized with alternate injections of cells from two human multiple myeloma (MM) cell lines. Screening by the enzyme-linked immunosorbent assay (ELISA) technique showed that MM4 reacted with human MM cell lines (7 of 7 positive), as well as bone marrow aspirates from MM patients (4 of 4 cases positive). MM4 did not react with marrow aspirates from control patients (3 cases), or with peripheral blood mononuclear (PBM) cells from normal subjects, lymphocytic (12 cases) and myelogenous (8 cases) leukemia patients. In addition, MM4 was negative with polymorphonuclear leukocytes and RBCs from normal donors. By means of the immunoperoxidase technique, the MM4-reactive antigen was detected in paraffin-embedded, Zenker formalin-fixed bone marrow biopsies of MM (12 of 12 cases positive), Waldenstrom's macroglobulinemia (2 of 2 cases positive), asymptomatic plasma cell dyscrasia (4 of 4 cases positive), and certain lymphomas (2 of 5 cases positive). Marrow biopsies from lymphocytic (5 cases) and myelogenous (5 cases) leukemias were uniformly negative. The MM4-reactive antigen also was expressed on plasma cells generated from pokeweed mitogen (PWM)-stimulated normal PBM cultures. The pattern of reactivity of MM4 with lymphocytes of B origin was similar to that of the plasma cell MoAb PCA-1. Competitive binding studies showed, however, that these two MoAbs recognized distinct antigenic determinants. These observations suggest that MM4 may be useful for the study of human plasma cell dyscrasias.

Survivin Expression, Regulation and Biological Role in Multiple Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1420-1420
Author(s):  
Mathilde Romagnoli ◽  
Régis Bataille ◽  
Sophie Barillé-Nion
Keyword(s):  
Cell Cycle ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Drug Resistance ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Survivin Expression ◽  
Drug Induced ◽  
Myeloma Cells ◽  
Stable Transfectants

Abstract Multiple myeloma (MM) is characterized by the accumulation within the bone marrow of malignant plasma cells with an enhanced survival capacity. Myeloma cells often develop drug resistance leading to treatment failure in patients. Survivin is a member of the inhibitor of apoptosis (IAP) gene family that has been implicated in both cell viability and regulation of mitosis in cancer cells. In this study, we have evaluated survivin expression and its biological involvement in viability, proliferation, cell cycle and drug resistance in myeloma cells. First by western blotting we detected survivin expression in 17 human myeloma cell lines (HMCL) from moderate level in the HMCL XG6 to strong level in the HMCL U266. Survivin was also detectable in primary myeloma cells purified from blood or bone marrow samples of 20 patients in contrast to purified B lymphocytes from tonsil samples or autologous EBV infected B lymphocytes. Survivin expression peaked at G2/M phase as obtained by drug-induced cell-cycle arrest. Second, we demonstrated that both major myeloma growth factors, IL-6 and IGF-1, induced upregulation of survivin expression through JAK/STAT and PI3K/AKT signalling pathways. In order to elucidate survivin role in myeloma cells, we established XG6 stable transfectants overexpressing survivin and extinguished survivin expression by siRNA in U266. Preliminary data suggest that survivin may participate in spontaneous cell death regulation, cell proliferation and drug sensitivity in those HMCL. In summary, our findings tend to show that survivin may be playing an important role in the pathogenesis of MM. A more defined understanding of survivin biology should enhance the rational development of drugs to inhibit its function in myeloma cells.

Activation Of Autophagy By Bone Marrow Adipocytes Protects Myeloma Cells From Chemotherapy-Induced Apoptosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1915-1915
Author(s):  
Jing Yang ◽  
Jingda Xu ◽  
Zhiqiang Liu ◽  
Jin He ◽  
Huan Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Stromal Cells ◽  
Conflicts Of Interest ◽  
High Dose ◽  
Caspase 9 ◽  
Drug Induced ◽  
Increased Risk ◽  
Induced Apoptosis

Abstract Currently, chemotherapy is the most effective treatment for multiple myeloma (MM). Although some new drugs have been shown to prolong survival in MM patients, these patients are prone to rapid relapse after high-dose treatment. Recent studies show that several bone marrow (BM) stromal cells are potentially involved in drug resistance. However, the role of other stromal cells is unclear. Adipocytes (ADs) are a major component of BM stromal cells. ADs have been shown to be involved in tumor rapid growth, metastasis, and apoptosis. Clinical studies suggest that BM ADs are associated with an increased risk of MM. Moreover, ADs isolated from patient BM biopsies were shown to support MM proliferation and migration. However, no published study has examined the importance of ADs in MM drug resistance. In addition, autophagy activation has been shown to induce drug resistance in cancer patients. We hypothesized that BM ADs protect MM cells from chemotherapy drug-induced apoptosis by autophagy activation. To examine the role of ADs in MM drug resistance, MM cells were cocultured with ADs at a ratio of 1:5 for 24 hours in medium with melphalan, dexamethasone, or bortezomib, the commonly used drugs for the treatment of MM. MM cells included primary MM cells isolated from BM aspirates of 5 MM patients and 6 MM cell lines. Human ADs were generated from mesenchymal stem cells derived from the BM mononuclear cells of healthy human fetal bones or BM aspirates of MM patients or healthy adult donors, cultured in AD medium for 2 weeks. ADs generated in vitro contained cytoplasmic Oil red O+ lipid droplets and produced triglycerol. Our results showed less drug-induced MM apoptosis in cocultures of MM cells and ADs compared with cultures of MM cells alone. Western blot analysis showed that treatment with melphalan upregulated the levels of cleaved caspase-9 and -3, but not -8, and PARP in MM cells. Compared with cultures alone, cocultures with ADs showed significantly lower levels of cleaved caspase-9, -3, and PARP in melphalan-treated MM cells. Mechanistic studies further showed that cocultures of ADs, compared with cultures alone, significantly upregulated the expression of autophagy proteins LC3B, Atg3, Atg5, and LAMP-1, but not Beclin-1. The addition of autophagy inhibitors 3-methyl adenine and chloroquine diphosphate to the cocultures remarkably enhanced apoptosis and caspase activation. Furthermore, we observed that cocultures of MM cells and ADs with either cell-cell contact or those separated by transwell inserts conferred similar protection from drug-induced apoptosis. We identified that AD-produced adipokines such as adiponection, leptin, adipsin, IL-6, MCP-1, TNF-a, and IGF-1, but not VEGF and CRP, were abundant in all examined ADs. Among these adipokines, adiponection, leptin, and adipsin were mainly produced from ADs and not from BM stromal cells, whereas other adipokines were produced from both cells. The addition of antibodies against these adipokines to the cocultures enhanced apoptosis and reduced autophagy, whereas addition of these adipokines to the cultures alone inhibited apoptosis and enhanced autophagy. In vivo studies validated these findings that injection of BM-derived ADs into the implanted human bones of SCID-hu mice bearing primary MM cells reduced response to treatment with melphalan and induced autophagy activation. Taken together, our findings elucidate a novel mechanism of MM drug resistance, through BM ADs. Our studies also provide evidence that targeting BM ADs may be a new approach to improve the efficacy of chemotherapy for the treatment of MM. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Characterization of a monoclonal antibody having selective reactivity with normal and neoplastic plasma cells

Blood ◽  
1987 ◽  
Vol 69 (1) ◽  
pp. 238-245 ◽  
Author(s):  
AW Tong ◽  
JC Lee ◽  
MJ Stone
Keyword(s):  
Monoclonal Antibody ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Plasma Cells ◽  
Pokeweed Mitogen ◽  
Enzyme Linked Immunosorbent Assay ◽  
Immunoperoxidase Technique ◽  
Binding Studies ◽  
Bone Marrow Biopsies

Abstract A myeloma cell-reactive monoclonal antibody (MoAb), MM4, was generated from BALB/c mice immunized with alternate injections of cells from two human multiple myeloma (MM) cell lines. Screening by the enzyme-linked immunosorbent assay (ELISA) technique showed that MM4 reacted with human MM cell lines (7 of 7 positive), as well as bone marrow aspirates from MM patients (4 of 4 cases positive). MM4 did not react with marrow aspirates from control patients (3 cases), or with peripheral blood mononuclear (PBM) cells from normal subjects, lymphocytic (12 cases) and myelogenous (8 cases) leukemia patients. In addition, MM4 was negative with polymorphonuclear leukocytes and RBCs from normal donors. By means of the immunoperoxidase technique, the MM4-reactive antigen was detected in paraffin-embedded, Zenker formalin-fixed bone marrow biopsies of MM (12 of 12 cases positive), Waldenstrom's macroglobulinemia (2 of 2 cases positive), asymptomatic plasma cell dyscrasia (4 of 4 cases positive), and certain lymphomas (2 of 5 cases positive). Marrow biopsies from lymphocytic (5 cases) and myelogenous (5 cases) leukemias were uniformly negative. The MM4-reactive antigen also was expressed on plasma cells generated from pokeweed mitogen (PWM)-stimulated normal PBM cultures. The pattern of reactivity of MM4 with lymphocytes of B origin was similar to that of the plasma cell MoAb PCA-1. Competitive binding studies showed, however, that these two MoAbs recognized distinct antigenic determinants. These observations suggest that MM4 may be useful for the study of human plasma cell dyscrasias.

Selective G-Protein Estrogen Receptor (GPER) Activation Triggers Anti-Multiple Myeloma Activity and Synergizes with MiR-29b-Inducing Drugs

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4725-4725
Author(s):  
Nicola Amodio ◽  
Marzia Leotta ◽  
Eugenio Morelli ◽  
Teresa Calimeri ◽  
Anna Maria Gullà ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Cell Lines ◽  
Plasma Cell ◽  
Protein Level ◽  
Plasma Cells ◽  
Microarray Dataset ◽  
Mrna Levels ◽  
Dose Dependent

Abstract Multiple myeloma (MM) is a plasma cell malignancy which remains incurable despite novel therapeutic approaches targeting both myeloma cells and their bone marrow milieu (BMM). MM cells express estrogen receptors (ER) belonging to both α and β isotypes and selective ER modulators or pure anti-estrogens have demonstrated therapeutic activity against this malignancy. GPER, formerly known as GPR30, is an orphan membrane-associated ER previously described to mediate non-genomic effects of estrogens and whose involvement in the pathophysiology of solid tumors is currently emerging. Here, we studied the expression pattern of GPER and the biological effects triggered by GPER activation using the synthetic compound G-1 ((±)-1-[(3aR*,4S*,9bS*)-4-(6-Bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H cyclopenta[c]quinolin-8-yl] ethanone), a selective GPER agonist (Tocris). We detected GPER expression in 9 out of 9 MM cell lines either at mRNA and protein level, as assessed by qRT-PCR and western blotting, respectively. By analysis of our microarray dataset based on plasma cells from 4 normal donors, 11 MGUS, 133 MM and 9 plasma cell leukemias (PCLs), we observed that GPER mRNA levels progressively declined during MM progression, since lower levels were found in PCL and MM samples as compared to healthy controls or MGUS. Interestingly, adhesion of MM cells to bone marrow stromal cells (BMSCs) reduced GPER mRNA levels, supporting a potential role of the BMM in regulating GPER expression. To address the relevance of GPER in modulating MM cell proliferation and/or death mechanisms, first we tested the GPER agonist G-1 in vitro. We found that G-1 inhibited, in a dose-dependent manner, proliferation of IL-6 dependent (INA-6) and independent (MM1R, MM1S, U266, RPMI-8226, NCI-H929, OPM2) MM cell lines, with an IC50 ranging from 2 to 5 microM, while did not affect the survival of peripheral blood mononuclear cells from healthy donors. G-1 treatment caused cell cycle arrest by increasing cells in G0 phase; moreover, it induced a significant and dose-dependent apoptotic cell death in all MM cell lines tested, as assessed by Annexin V/7AAD staining and western blot analysis of active caspases 3, 7 and 9. G-1 promoted the expression of autophagic markers like Beclin-1 and LC3A/B, the cytosolic punctate pattern of LC3B and down-regulated p62/SQSTM-1 expression, indicating functional involvement of GPER in autophagy. Moreover, GPER transduced rapid non-genomic signaling through MAPKs, since G-1-mediated GPER activation triggered phosphorylation of ERK1/2 already after 15’ treatment in MM1S and U266 cells. Importantly, i.p. injection of G-1 (2mg/kg) in SCID mice significantly reduced the growth of subcutaneous MM1S xenografts, as compared to vehicle-treated animals. We next evaluated whether G-1-induced effects could be associated to modulation of miRNA levels in MM cells. Indeed, we found that G-1 up-regulated the tumor suppressor miR-29b; this effect was likely a consequence of the down-regulation of the miR-29b transcriptional inhibitor Sp1, whose mRNA and protein levels were reduced after G-1 treatment. Consistently, an inverse correlation between GPER and Sp1 mRNA levels in MM patient plasma cells could be gathered from our microarray dataset. In addition, miR-29b canonical targets, like CDK6 and MCL-1, were down-regulated at protein level in G-1-treated MM cell lines. Finally, we demonstrated that G-1 synergizes with established miR-29b-inducing compounds, like bortezomib and vorinostat, in the inhibition of MM cell survival. Taken together, our results indicate that the GPER agonist G-1 is a novel powerful anti-tumor compound enriching the repertoire of investigative anti-MM agents, and further strengthen the role of miR-29b as effector of anti-MM drugs. Disclosures No relevant conflicts of interest to declare.

Spironolactone-Induced Agranulocytosis

1997 ◽  
Vol 31 (5) ◽  
pp. 582-585 ◽  
Author(s):  
Anna M Whitling ◽  
Pablo E Pérgola ◽  
John Lee Sang ◽  
Robert L Talbert
Keyword(s):  
Risk Factors ◽  
Adverse Effect ◽  
Bone Marrow ◽  
Leukocyte Count ◽  
Laboratory Data ◽  
University Hospital ◽  
Drug Induced ◽  
Bone Marrow Biopsies ◽  
Case Summary ◽  
Before And After

OBJECTIVE: TO report a case of agranulocytosis secondary to spironolactone in a patient with cryptogenic liver disease. CASE SUMMARY: A 58-year-old Hispanic woman with cryptogenic cirrhosis was admitted to University Hospital on October 31, 1995. Laboratory data revealed a leukocyte count of 1.0 × 103/mm3 and an absolute neutrophil count (ANC) of 10 cells/mm3. Prior to treatment with spironolactone, the leukocyte count was 10.2 × 103/mm3 and ANC 8400 cells/mm3. Agranulocytosis resolved 5 days following the discontinuation of spironolactone. Results from the bone marrow biopsies before and after treatment with spironolactone suggested that agranulocytosis was caused by the drug's toxic effect on the bone marrow. DISCUSSION: Drug-induced agranulocytosis is a serious adverse effect, occurring at a rate of approximately 6.2 cases per million persons each year. In addition to the case reported here, three other reports of agranulocytosis secondary to spironolactone have been published in the literature. Several factors have been identified that may increase a patient's risk for developing agranulocytosis, including increased age, hepatic or renal impairment, drag dosage and duration, and concurrent medications. CONCLUSIONS: Agranulocytosis secondary to spironolactone is a serious potential adverse effect. Patients with risk factors for developing this adverse effect should be closely monitored since early detection and discontinuation of spironolactone can improve prognosis.

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