Translational profiling in multiple myeloma to identify novel therapeutic targets
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE59080 | GEO | 2014/07/04
SECONDARY ACCESSION(S): PRJNA254342
REPOSITORIES: GEO
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Project description:The goal of this study is to identify translationally-regulated mRNAs in multiple myeloma following treatment with dexamethasone The overall design is to treat the multiple myeloma cell line MM1.S with 1uM dexamethasone for 0 or 4 hours and collect total RNA and fractionated polysome pooled RNA (in 3 fractions)
2014-07-04 | E-GEOD-59080 | biostudies-arrayexpress
Project description:The introduction of novel therapeutic agents has considerably improved the median survival of patients with multiple myeloma (MM). However, the natural history of the disease is characterized by continuous relapses over time. As a consequence, the development of new drugs is still required to treat MM recurrence. Here, we report for the first time the potent anti-myeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. Amilorideinduced apoptosis was observed in a broad panel of MM cell lines and in xenograft mouse models. Moreover, amiloride also had a synergistic effect when combined with dexamethasone and melphalan. RNA-seq experiments showed that amiloride not only significantly altered the level of transcript isoforms and alternative splicing events, but also deregulated the spliceosomal machinery. Additionally, disruption of the splicing machinery in immunofluorescence studies was associated with the inhibition of myeloma cell viability after amiloride exposure. Although amiloride was able to induce apoptosis in myeloma cells lacking p53 expression, activation of p53 signaling was observed in wild-type and mutated TP53 cells after amiloride exposure. On the other hand, the manageable toxicity profile of amiloride is well known and we did not find a significant systemic toxicity in mice treated with amiloride. Overall, our results provide a mechanistic rationale for the use of amiloride as an alternative treatment option for relapsed MM patients.
2018-09-10 | GSE95077 | GEO
Project description:SUMOylation inhibition overcomes dexamethasone resistance in multiple myeloma
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Project description:The combination of bortezomib and dexamethasone should become the reference induction treatment for multiple myeloma patients younger than 65 years. Pharmacogenomic profiles of genes involved in response to treatment may help to understand resistance. We performed gene expression profiling in 9 myeloma cell lines, incubated or not with bortezomib and dexamethasone for 6 hours. Supervised analysis identified significantly up regulated genes involved in stress responses. We focused on REDD1 a gene known to be rapidly induced by a wide variety of stress conditions and DNA damages. REDD1 expression was early and highly induced after bortezomib exposure. REDD1 induction was associated with the dephosphorylation of P70 S6 ribosomal kinase (P70S6K), a key substrate of mTOR. These effects were dependent upon cell line. REDD1 was overexpressed within two hours in bortezomib resistant cell lines in association with a cell size decrease. In sensitive cell lines, neither REDD1 induction nor morphological changes occurred. RNA interference mediated inhibition of REDD1 induction abrogates P70S6K dephosphorylation, early transitory cell size reduction and enhances sensitivity to bortezomib - dexamethasone. Our results suggest that mTOR regulation could be a resistance mechanism mediated by REDD1 expression in myeloma cells. Nine cell lines of multiple myeloma studied, incubated or not with bortezomib and dexamethasone, examined with spotted cDNA nylon membrane. Cell line and Code : JJN3 = Vel_1x; L363 = Vel_2x; LP1 = Vel_3x; MDN = Vel_4x; NCI = Vel_5x; RPMI = Vel_6x; SBN = Vel_7x; U266 = Vel_8x; XG1 = Vel_9x.
2010-02-14 | E-GEOD-11866 | biostudies-arrayexpress
Project description:Lactoferrin-derived peptide chimera, LF chimera (LFch) is a synthetic peptide that mimics the functional unit of lactoferrin with antibacterial activity. Since antimicrobial peptides (AMPs) are known to be promising candidates for cancer treatment, in this study, we explored the potential of LFch for the treatment of multiple myeloma (MM), a malignant clonal plasma cell disease of the bone marrow. LFch effectively inhibited MM1S, MM1R, and RPMI8226 multiple myeloma cell growth and induced the early and late phase of apoptosis whereas did not a normal PBMCs. Furthermore, LFch modulated the relative gene expression of survival, apoptosis, and mitochondrial dysfunction at the transcriptional levels.
2025-02-19 | GSE273287 | GEO
Project description:This Series represents the gene expression profiles of patients with multiple myeloma who have been treated previously. In brief, Total Therapy 6 (TT6) is an open label phase 2 protocol for patients with symptomatic multiple myeloma, who had been treated with more than one cycle of prior therapy excluding autologous hematopoietic stem cell transplant. This protocol was approved by the institutional review board on March 25, 2009 (IRB#108053). The TT6 treatment regimen consists of induction therapy with Melphalan/Bortezomib/Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (M-VTD-PACE) followed by a high dose M-VTD-PACE based tandem transplant. Maintenance therapy consists of Bortezomib/Lenalidomide/Dexamethasone alternating with Borteomib/Melphalan/Dexamethasone every months for 3 years.
2015-01-20 | GSE57317 | GEO
Project description:This Series represents the gene expression profiles of patients with multiple myeloma who have been treated previously. In brief, Total Therapy 6 (TT6) is an open label phase 2 protocol for patients with symptomatic multiple myeloma, who had been treated with more than one cycle of prior therapy excluding autologous hematopoietic stem cell transplant. This protocol was approved by the institutional review board on March 25, 2009 (IRB#108053). The TT6 treatment regimen consists of induction therapy with Melphalan/Bortezomib/Thalidomide/Dexamethasone/Cisplatin/Doxorubicin/Cyclophosphamide/Etoposide (M-VTD-PACE) followed by a high dose M-VTD-PACE based tandem transplant. Maintenance therapy consists of Bortezomib/Lenalidomide/Dexamethasone alternating with Borteomib/Melphalan/Dexamethasone every months for 3 years. We analyzed CD138+ selected cells of previously treated MM patients by microarray.
2015-01-20 | E-GEOD-57317 | biostudies-arrayexpress
Project description:Protein homeostasis is critical to the survival of multiple myeloma (MM) cells. While this is targeted with proteasome inhibitors, mRNA translation inhibition has not entered trials. Recent work illustrates broad sensitivity MM cells to translation inhibitor omacetaxine. We hypothesized that understanding how MM cells become omacetaxine resistant will lead to the development of drug combinations to prevent or delay relapse. We generated omacetaxine resistance in H929 and MM1S MM cell lines and compared them to their parental lines. Resistant lines displayed decreased sensitivity to omacetaxine, with EC50 > 100 nM, compared to parental line sensitivity of 24-54 nM. To adapt to omacetaxine, H929 and MM1S exhibited an increased percentage of multi-nucleated polyaneuploid cells that led to distinct molecular mechanisms of resistance Interestingly, both resistant lines showed a defect in oncologic potential via extended survival in a MM xenograft model. Since omacetaxine inhibits protein synthesis, we performed both RNA-sequencing and ribosome profiling (Ribo-seq) to identify shared and unique regulatory strategies of resistance. Transcripts encoding translation factors and containing TOP motifs in their 5’ UTR were translationally upregulated in both resistant cell lines. The mTOR pathway promotes the translation of TOP motif containing mRNAs. Indeed, mTOR inhibition restored partial sensitivity to omacetaxine in both MM1S and H929 cells. Primary MM cells from patient samples were sensitive to combinations of omacetaxine and mTOR inhibitors rapamycin and Torin 1. These results provide a rational approach for omacetaxine-based combination in patients with multiple myeloma, which have historically shown better responses to multi-agent regimens.
2025-01-27 | GSE263767 | GEO
Project description:One of the cornerstone drugs in the treatment of multiple myeloma (MM) are glucocorticoids. Because MM cells hijack the bone marrow microenvironment to obtain growth and survival signals, resistance to glucocorticoid-induced apoptosis emerges, yet, the underlying mechanisms remain poorly characterized. Here we identify that the chemokine receptor CCR1 together with its main ligand CCL3, plays a pivotal role in reducing glucocorticoid sensitivity of MM cells. We show that blocking of CCR1 signalling with the antagonist BX471 enhances the anti-MM effects of the glucorticoid dexamethasone in several MM cell lines, primary patient material and in a myeloma xenograft mouse model. Mechanistically, the drug combination shifts the balance between pro- and antiapoptotic proteins towards apoptosis and deregulates lysosomal proteins. We further find that the glucocorticoid-induced downregulation of CCR1 mRNA and protein is blunted in a glucocorticoid-resistance onset model. Finally, we demonstrate that CCR1 inhibition partially reverses GC-resistance, hereby offering a viable glucocorticoid resensitization strategy for MM treatment.
2025-06-18 | PXD055337 | Pride