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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

SUBMITTER: Esteban Braggio

PROVIDER: E-GEOD-31451 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

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

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

2011-10-01 | GSE31451 | GEO

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

2011-10-01 | GSE31421 | GEO

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

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

CRL4(CRBN) ubiquitin ligase profiling

Project description:In the 1950s the drug thalidomide administered as a sedative to pregnant women led ot the birth of thousands of children with multiple defects. Despite its teratogenicity, thalidomide and ist IMiD derivatives recently emerged as effective treatments for multiple myeloma and 5q-dysplasia. IMiDs target the CUL4-RBX1-DDB1-CRBN (CRL4(CRBN)) ubiquitin ligase. Through an unbiased screen we identify the homeobox trranscription factor MEIS2 as an endogenous substrate of CRL4(CRBN). By definition, a specific target of CRL4(CRBN) is expected to have a very low intensity on negative control arrays (E1_E2), (E1_CRBN), (E1_E2_Cdt2), (E1_E2_Cdt2_revlimid), (E1_E2_Cdt2_CSN) or with CRL4(CRBN) in presence of inhibitor (E1_E2_CRBN_revlimid) and high intensity on arrays with CRL4(CRBN) (E1_E2_CRBN) or CRL4(CRBN) in presence of CSN (E1_E2_CRBN_CSN) Accordingly 16 protein microarrays were subjected to in vitro ubiquitylation using the following enzyme combinations: 3x Uba1+UbcH5a; 2x Uba1+UbcH5a+CRL4(DDB2); 3x Uba1+UbcH5a+CRL4(CRBN); 2x Uba1+UbcH5a+CRL4(CRBN)+lenalidomide; 2x Uba1+UbcH5a+CRL4(CRBN)+CSN; 2x Uba1+UbcH5a+CRL4(Cdt2); 1x Uba1+UbcH5a+CRL4(Cdt2)+CSN; 1x Uba1+UbcH5a+CRL4(Cdt2)+lenalidomide

2014-05-13 | E-GEOD-57554 | biostudies-arrayexpress

Maturation of the thalidomystery

Project description:Gene expression profile (GEP) was analyzed from cultured bone marrow (BM) samples of patients with lenalidomide-responsive versus lenalidomide-resistant myeloma after 24 hours incubation in vitro with thalidomide (Thal) (0.8 Âµg/ml), lenalidomide (Len) (0.5 Âµg/ml) or with DMSO (control). Comparative gene expression profile of cultured bone marrow samples from patients with lenalidomide responsive versus lenalidomide resistant myeloma after 24 hours incubation in vitro with thalidomide, lenalidomide or DMSO (control).

2014-08-26 | E-GEOD-60742 | biostudies-arrayexpress

Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma

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

pSILAC mass spectrometry reveals ZFP91 as novel IMiD dependent substrate of the CRL4CRBN ligase

Project description:Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of hematologic malignancies. It was shown that IMiDs impart gain of function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKFZ1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish that ZFP91 is a bona fide IMiD dependent CRL4CRBN substrate and further show that ZFP91 harbors a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC-MS) is a sensitive approach for target identification of small molecules inducing selective protein degradation.

2017-03-01 | GSE94728 | GEO

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

pSILAC mass spectrometry reveals ZFP91 as novel IMiD dependent substrate of the CRL4CRBN ligase - PART 2

Project description:Thalidomide and its derivatives lenalidomide and pomalidomide (IMiDs) are effective treatments of hematologic malignancies. It was shown that IMiDs impart gain of function properties to the CUL4-RBX1-DDB1-CRBN (CRL4CRBN) ubiquitin ligase that enable binding, ubiquitination and degradation of key therapeutic targets such as IKFZ1, IKZF3 and CSNK1A1. While these substrates have been implicated as efficacy targets in multiple myeloma (MM) and 5q deletion associated myelodysplastic syndrome (del(5q)-MDS), other targets likely exist. Using a pulse-chase SILAC mass spectrometry-based proteomics approach, here we demonstrate that lenalidomide induces the ubiquitination and degradation of ZFP91. We establish that ZFP91 is a bona fide IMiD dependent CRL4CRBN substrate and further show that ZFP91 harbors a zinc finger (ZnF) motif, related to the IKZF1/3 ZnF, critical for IMiD dependent CRBN binding. These findings demonstrate that single time point pulse-chase SILAC mass spectrometry-based proteomics (pSILAC-MS) is a sensitive approach for target identification of small molecules inducing selective protein

2017-05-29 | PXD005857 | Pride

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