Lenalidomide-induced changes in gene expression profile of multiple myeloma cells
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PROVIDER: PRJNA782661 | ENA |
REPOSITORIES: ENA
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Project description:We identified lenalidomide-induced changes in gene expression profile to identify IKZF1-regulated genes in multiple myeloma.
2022-11-18 | GSE189365 | GEO
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
Project description:The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. 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 to investigate non-genetic resistance mechanisms. These analyses revealed a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduced sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. In conclusion, we found upregulation of CDK6 to cause lenalidomide resistance in multiple myeloma that can be overcome by pharmacological intervention.
2021-12-17 | PXD021265 | Pride
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.
2021-12-14 | GSE162403 | GEO
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:Krönke J, Udeshi ND, Narla A, Grauman P, Hurst SN, McConkey M, Svinkina T, Heckl D, Comer E, Li X, Ciarlo C, Hartman E, Munshi N, Schenone M, Schreiber SL, Carr SA, Ebert BL. Science 2014, 343, 301-305. doi:10.1126/science.1244851.
Lenalidomide is a drug with clinical efficacy in multiple myeloma and other B cell neoplasms, but its mechanism of action is unknown. Using quantitative proteomics, we found that lenalidomide causes selective ubiquitination and degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase. IKZF1 and IKZF3 are essential transcription factors in multiple myeloma. A single amino acid substitution of IKZF3 conferred resistance to lenalidomide-induced degradation and rescued lenalidomide-induced inhibition of cell growth. Similarly, we found that lenalidomide-induced interleukin-2 production in T cells is due to depletion of IKZF1 and IKZF3. These findings reveal a previously unknown mechanism of action for a therapeutic agent: alteration of the activity of an E3 ubiquitin ligase, leading to selective degradation of specific targets.
2015-01-26 | MSV000079017 | MassIVE
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.
2021-01-27 | GSE165557 | GEO
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:This SuperSeries is composed of the following subset Series: GSE31421: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [expression profiling] GSE31451: Cereblon expression is required for the anti-myeloma activity of lenalidomide and pomalidomide [aCGH] Refer to individual Series
2011-09-30 | E-GEOD-31452 | biostudies-arrayexpress
Project description:Gene expression changes between lenalidomide (LEN)-sensitive and LEN-resistant human multiple myeloma (MM) cell lines
| PRJNA922036 | ENA