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Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE11866 | GEO | 2010/02/15

SECONDARY ACCESSION(S): PRJNA105673

REPOSITORIES: GEO

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Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

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

Gene expression profiles of patients with multiple myeloma who have been treated previously

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

Homo sapiens

Project description:Bortezomib inhibits mTOR pathway in multiple myeloma cells via induced expression of REDD1.

| PRJNA105673 | ENA

Gene expression profiles of patients with multiple myeloma who have been treated previously

2015-01-20 | E-GEOD-57317 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [human cell lines].

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment (33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this part of the study, we identify signatures of bortezomib sensitivity by gene expression profiling (GEP) using The human myeloma cell lines MM1.S and U266 (obtained from ATCC). Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in two myeloma cell lines.

2013-07-02 | E-GEOD-41929 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines II]

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment(33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in Multiple Myeloma derived cell lines.

2013-07-02 | E-GEOD-41928 | biostudies-arrayexpress

Genome-wide analysis of gene expression in response to bortezomib treatment [mouse cell lines I]

Project description:Genome-wide analysis of gene expression in response to bortezomib treatment (33 nM) in cell lines before and after selection for resistance. Multiple myeloma (MM) is a hematologic malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow. While the first-to-market proteasome inhibitor bortezomib/VELCADE has been successfully used to treat myeloma patients, drug resistance remains an emerging problem. In this study, we identify signatures of bortezomib sensitivity and resistance by gene expression profiling (GEP) using pairs of bortezomib-sensitive and -resistant cell lines created from the Bcl-XL/Myc double transgenic mouse model of MM. Finally, these data reveal complex heterogeneity within MM and suggest resistance to one drug class reprograms resistant clones to make them more sensitive to a distinct class of drugs. This study represents an important next step in translating pharmacogenomic profiling and may be useful for understanding personalized pharmacotherapy of MM patients. Transcript profiling timecourses after treatment with Bortezomib treatment (33nm) in Multiple Myeloma derived cell lines.

2013-07-02 | E-GEOD-41927 | biostudies-arrayexpress

Jumonji Demethylase Inhibitor GSK-J4 treated Multiple Myeloma JJN3 and RPMI

Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib

2016-08-21 | GSE60600 | GEO

Transcription profiling of human samples from multiple myeloma patients treated with bortezomib or dexamethasone

Project description:The aims of this study were to assess the feasibility of prospective pharmacogenomics research in multicenter international clinical trials of bortezomib in multiple myeloma and to develop predictive classifiers of response and survival with bortezomib. Patients with relapsed myeloma enrolled in phase 2 and phase 3 clinical trials of bortezomib and consented to genomic analyses of pretreatment tumor samples. Bone marrow aspirates were subject to a negative-selection procedure to enrich for tumor cells, and these samples were used for gene expression profiling using DNA microarrays. Data quality and correlations with trial outcomes were assessed by multiple groups. Gene expression in this dataset was consistent with data published from a single-center study of newly diagnosed multiple myeloma. Response and survival classifiers were developed and shown to be significantly associated with outcome via testing on independent data. The survival classifier improved on the risk stratification provided by the International Staging System. Predictive models and biologic correlates of response show some specificity for bortezomib rather than dexamethasone. Informative gene expression data and genomic classifiers that predict clinical outcome can be derived from prospective clinical trials of new anticancer agents. Experiment Overall Design: Purified myeloma samples were collected prior to enrolment in clinical trials of bortezomib (PS-341). Samples were subject to replicate gene expression profiling using the Affymetrix 133A/B microarray. Data was normalized in MAS5.0 and the median of replicates is reported. Data was normalized to a Ttimmed mean of 15o and is NOT log transformed. Various patient parameters are reported as well as response, TTP and survival upon treatment with bortezomib or dexamethasone.

2008-06-17 | E-GEOD-9782 | biostudies-arrayexpress

RNA-Seq of newly diagnosed patients in the PADIMAC study leads to a bortezomib/lenalidomide decision signature

Project description:Improving outcomes in multiple myeloma will not only involve development of new therapies, but better use of existing treatments. We performed RNA sequencing (RNA-Seq) on samples from newly diagnosed patients enrolled into the phase II PADIMAC study. Using an empirical Bayes approach and synthetic annealing, we developed and trained a seven-gene signature to predict treatment outcome. We tested the signature on independent cohorts treated with bortezomib- and lenalidomide-based therapies. The signature was capable of distinguishing which patients would respond better to which regimen. In the CoMMpass dataset, patients who were treated correctly according to the signature had a better progression-free and overall survival than those who were not. Indeed, the outcome for these correctly treated patients was non-inferior to those treated with combined bortezomib, lenalidomide, and dexamethasone (VRD). PADIMAC: Bortezomib, Adriamycin and Dexamethasone (PAD) therapy for previously untreated patients with multiple myeloma: Impact of minimal residual disease (MRD) in patients with deferred ASCT (autologous stem cell transplant)

2018-06-28 | GSE116324 | GEO

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