The BET bromodomain inhibitor CPI203 improves lenalidomide activity in in vitro and in vivo models of multiple myeloma by synergistic blockade of Ikaros and c-Myc signaling
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE87403 | GEO | 2016/09/28
SECONDARY ACCESSION(S): PRJNA344666
REPOSITORIES: GEO
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Project description:We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34+ cells and from CD34+ cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number burst-forming units-erythroid (BFU-E), while lenalidomide specifically increased colony-forming units-erythroid (CFU-E). Use of the drugs in combination demonstrates that their effects are not redundant.
2011-04-28 | GSE28896 | GEO
Project description:We explored the effects of dexamethasone and lenalidomide, individually and in combination, on the differentiation of primary human bone marrow progenitor cells in vitro. Both agents promote erythropoiesis, increasing the absolute number of erythroid cells produced from normal CD34+ cells and from CD34+ cells with the types of ribosome dysfunction found in DBA and del(5q) MDS. However, the drugs had distinct effects on the production of erythroid progenitor colonies; dexamethasone selectively increased the number burst-forming units-erythroid (BFU-E), while lenalidomide specifically increased colony-forming units-erythroid (CFU-E). Use of the drugs in combination demonstrates that their effects are not redundant. Human CD34+ cells were cultured for 48 hours in the erythroid differentiation media described above with the addition of 40 ng/mL of FMS-like tyrosine kinase 3 (flt-3; Miltenyi Biotech) and 15 ng/mL of Granulocyte colony-stimulating factor (G-CSF; Amgen). Cells were cultured in the presence of the drugs of interest for 24 hours. RNA was purified using Trizol (Invitrogen). RNA was amplified and labeled by in vitro transcription and hybridized to the Affymetrix HT Human Genome U133A Array. Three replicates per condition.
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Project description:Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma (MM); however, gene expression profiling (GEP) based signatures may enable more specific risk categorization. We examined the utility of two GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. The E4A03 clinical trial randomized patients with previously untreated MM to lenalidomide and either standard-dose dexamethasone. Baseline bone marrow samples were obtained from consenting patients. The marrow aspirates were subjected to a fully automated ROBOSEP cell separation system that utilizes immunomagnetic technology to positively select for CD 138+ cells. The purity of the sorting was confirmed by 3-color immunofluorescent slide based assessment on the sorted cells. The plasma cell gene expression profiles were analyzed using U133 Plus 2.0 array. All samples were run individually with no pooling. The GEP-70 signature was determined as previously described, using log2 transformed raw MAS 5.0 signals. The GEP15 classification was performed as previously described, with the patients in highest quartile for the risk score being considered as high risk.
2011-08-25 | E-GEOD-31504 | biostudies-arrayexpress
Project description: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.
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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
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.
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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 15 samples from multiple myeloma cell lines.
2011-09-30 | E-GEOD-31421 | biostudies-arrayexpress
Project description:Multiple myeloma is a genetically heterogeneous disease of plasma cells. The thalidomide analog lenalidomide is a mainstay in the treatment of multiple myeloma and is used in combination with other drugs such as corticosteroids, chemotherapy and proteasome inhibitors, achieving high remission rates. However, most patients relapse due to acquired resistance of the malignant cells. Genetic analyses have revealed mutations in CRBN, the target of all IMiDs, as a resistance mechanism in 10% of patients, while for the majority of cases, the mechanism of resistance is unknown. Here, we performed integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses revealed proteins highly upregulated at relapse, including TRIP13, RRM1 and CDK6, which was not reflected on the RNA expression level. Overexpression of CDK6 in multiple myeloma cell lines reduced sensitivity to lenalidomide and pomalidomide in a kinase-dependent fashion. CDK6 inactivation by palbociclib or a CDK6-specific proteolysis targeting chimera (PROTAC) plus lenalidomide or pomalidomide was highly synergistic. Proteomic analyses in cell lines revealed that CDK6 inhibition reverses a complex protein resistance signature including RRM1 and TRIP13 and in combination with IMiDs promotes metabolic remodeling and c-MYC downregulation . In conclusion, our global proteomic analyses identified CDK6 upregulation as a drug target to overcome lenalidomide resistance in multiple myeloma.
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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.
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