Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNA-seq of human multiple myeloma cell lines and cell lines with long-term exposure to lenalidomide

ABSTRACT: Multiple myeloma (MM) is a hematopoietic malignancy whose prognosis has been improved by immunomodulatory drugs (IMiDs); however, long-term exposure of these drugs caused drug resistance in MM patients. Here we applied RNA sequencing to analyze the novel mechanisms of the acquiring lenalidomide resistance in MM cell lines. Firstly, lenalidomide resistant cell lines were established by long-term exposure of lenalidomide nearly 1 year. Comparative analysis between resistant and sensitive cell lines revealed that the resistant cells secreted a greater number of exosomes and enhanced cell adhesion ability. By whole transcriptome analysis, snare interaction pathway, which was associated with exosome secretion, was enriched in lenalidomide resistant cell lines. Finally, we identified SORT1 and LAMP2, which increased exosome secretion and cell adhesion ability in lenalidomide resistant cells. Notably, silencing of SORT1 or LAMP2 ameliorated the lenalidomide sensitivity in the resistant cells. In conclusion, our results showed that exosome secretion via SORT1 or LAMP2 could induce cell adhesion, leading to the acquisition of lenalidomide resistance in MM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165557 | GEO | 2021/01/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Treatment of MM cells with IMiDs or reducing the expression of EIF2C2 significantly affects steady-state levels of miRNAs

Project description:Lenalidomide is a therapeutically active compound that binds to E3 ubiquitin ligase recruiter cereblon (CRBN) and induces cytotoxicity. We have identified eukaryotic translation initiation factor 2 subunit C2 (EIF2C2) as a new member of CRBN-downstream binding protein that plays an important role in microRNA (miRNA) maturation and function. The treatment of immunomodulatory drug (IMiD)-sensitive multiple myeloma (MM) cells with lenalidomide altered the steady-state levels of CRBN, EIF2C2 and miRNAs and induced apoptosis. However, although the treatment of IMiD-resistant MM cells with lenalidomide altered the steady-state levels of CRBN, EIF2C2 and miRNAs, but did not massively induce apoptosis. In contrast, silencing of EIF2C2 with its small hairpin RNA significantly altered the levels of miRNAs and induced apoptosis regardless of whether those cells are sensitive or resistant to IMiDs. Therefore, EIF2C2 could be considered as a new drug target for overcoming IMiDs resistance in MM cells. To find the role of EIF2C2 in MM cell growth, OCI-My5 cell lines My5/LV and My5/CRBN, with low and high CRBN expression, respectively, were treated 12 different ways. The steady-state levels of miRNAs between (1) My5/LV, EIF2C2-shRNA-treated My5/LV and EIF2C2-cDNA-treated My5/LV cells, (2) My5/CRBN, EIF2C2-shRNA-treated My5/CRBN and EIF2C2-cDNA-treated My5/CRBN cells, (3) My5/LV cells, My5/LV cells treated with 10 ÂµM lenalidomide for 72 hours or 120 hours, and EIF2C2-cDNA-treated My5/LV cells treated with 10 ÂµM lenalidomide for 72 hours, and (4) My5/CRBN cells, My5/CRBN cells treated with 10 ÂµM lenalidomide for 72 hours or 120 hours, and EIF2C2-cDNA-treated My5/CRBN cells treated with 10 ÂµM lenalidomide for 72 hours, were compared in this array.

2016-03-09 | E-GEOD-61693 | biostudies-arrayexpress

Identification of Lenalidomide resistance pathways in Myeloma and targeted re-sensitization using Cereblon replacement, inhibition of STAT3 or targeting of IRF4

Project description:In the present study, we established four lenalidomide resistant HMCLs by culturing IMiD responsive HMCLs in the presence of lenalidomide for an extended time. Those resistant cell lines were studied along with their isogenic-sensitive lines to identify the genetic pathways underlying changes associated with resistance. Here mRNAseq was performed to detect the gene expression changes in XG1LenRes compared with its IMiDs sensitive parental cell line XG1.

2019-12-07 | GSE123506 | GEO

Treatment of MM cells with IMiDs or reducing the expression of EIF2C2 significantly affects steady-state levels of miRNAs

2016-03-09 | GSE61693 | GEO

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH]

Project description:The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their anti-tumor effects remains unclear. We investigated the role of cereblon (CRBN), a primary teratogenic target of thalidomide, in the anti-myeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to and putatively resistant to lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity, and a possible biomarker for the clinical assessment of anti-myeloma efficacy. We included two isogenic MM1.S cell lines, which differ in the sensibiligy to lenalidomide. We included MM1.S and MM1.S res, which were sensitive and resistant to lenalidomide, respectively.

2011-09-30 | E-GEOD-31451 | biostudies-arrayexpress

Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling]

2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress

Single cell RNA-seq of relapsed and refractory multiple myeloma patients defines new resistance pathways and targeted treatments

Project description:Multiple myeloma (MM) is a neoplastic plasma cell (PC) disorder, characterized by clonal proliferation of malignant PC. Despite extensive research, disease heterogeneity within and between treatment resistant patients is poorly characterized. Here, we conduct a prospective multi-center single-arm clinical trial (NCT04065789), combined with longitudinal single cell RNA-seq to study the molecular dynamics of MM resistance mechanisms. Forty-one newly diagnosed MM patients who either failed to respond or experienced early relapse after a bortezomib-containing induction regimen, were enrolled to evaluate the safety and efficacy of a daratumumab/carfilzomib/lenalidomide/dexamethasone combination. Primary clinical endpoint was safety and tolerability. Secondary endpoints included overall response rate; progression free survival, and overall survival. Treatment was safe and well-tolerated, deep and durable responses were achieved. In prespecified exploratory analyses, comparison of 41 primary-refractory and early-relapsed patients with 11 healthy subjects and 15 newly diagnosed MM patients revealed new MM molecular pathways of resistance, including hypoxia tolerance, protein folding, and mitochondria respiration, that generalized to larger clinical cohorts (CoMMpass). We found peptidylprolyl isomerase A (PPIA), a central gene in the protein-folding response pathway, as a potential new target for resistant MM. CRISPR/Cas9 deletion of PPIA or inhibition of PPIA with cyclosporin A significantly sensitizes MM tumor cells to proteasome inhibitors. Together, our study defines a roadmap for integrating scRNA-seq in clinical trials, identifies a signature of highly resistant MM patients and discovers PPIA as a potent therapeutic target for these tumors.

2021-01-27 | GSE161195 | GEO

ZFP91 and IKZF1 Cooperatively Promote IMiD Resistance in T-Cell Lymphomas

Project description:The immunomodulatory (IMiD) agents, such as lenalidomide, are highly effective treatment for several B cell lymphomas but have poor efficacy in T cell lymphomas (TCLs). Here, we show that IKZF1 is a key drug target and vulnerability in lenalidomide sensitive TCL cells. However, TCLs are largely resistant and become less dependent on IKZF1. Instead, ZPF91 functions as a transcription factor (TF) and coregulates cell survival with IKZF1 in TCL cells that develop resistance to lenalidomide. Aberrant upregulation of CSNK2B, which leads to c-Jun inactivation, contributes to an enhanced TF activity of ZFP91 and suppresses immune activation triggered by lenalidomide. Although ZFP91 can be better targeted by pomalidomide compared to lenalidomide, an inefficient degradation of IKZF1 and ZFP91 widely exists among IMiD-resistance TCLs. A novel CELMoD agent CC-92480, with markedly increased potency and similar substrate selectivity, can overcome IMiD-resistance across multiple TCL subtypes by near complete degradation of IKZF1 and ZFP91.

2022-04-21 | GSE172505 | GEO

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.

2013-07-02 | GSE41927 | GEO

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.

2013-07-02 | GSE41928 | GEO

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

Project description:Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

2020-04-13 | GSE123660 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data