Identification of Lenalidomide resistance pathways in Myeloma and targeted re-sensitization using Cereblon replacement, inhibition of STAT3 or targeting of IRF4
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ABSTRACT:
PROVIDER: PRJNA508958 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8308153_1.fastq.gz | Fastqsanger.gz | |||
| SRR8308153_2.fastq.gz | Fastqsanger.gz | |||
| SRR8308154_1.fastq.gz | Fastqsanger.gz | |||
| SRR8308154_2.fastq.gz | Fastqsanger.gz | |||
| SRR8308155_1.fastq.gz | Fastqsanger.gz |
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Similar Datasets
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: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: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: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
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.
2011-10-01 | GSE31451 | 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.
2011-10-01 | GSE31421 | 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:To understand immunomodulatory drug (IMiD) resistance in multiple myeloma (MM), we created isogenic human multiple myeloma cell lines (HMCLs) sensitive and resistant to lenalidomide, respectively. Four HMCLs were demonstrated to be resistant to all IMiDs including lenalidomide, pomalidomide, and CC-220, but not to Bortezomib. In three HMLCs (MM.1.SLenRes, KMS11LenRes and OPM2LenRes), CRBN abnormalities were found, including chromosomal deletion, point mutation, and low CRBN expression. The remaining HMCL, XG1LenRes, showed no changes in CRBN but exhibited CD147 upregulation and impaired IRF4 downregulation after lenalidomide treatment. Depletion of CD147 in XG1LenRes and three additional HMCLs had no significant impact on MM viability and lenalidomide response. Further analysis of XG1LenRes demonstrated increased IL6 expression and constitutive STAT3 activation. Inhibition of STAT3 with a selective compound (PB-1-102) re-sensitized XG1LenRes to lenalidomide. Since XG1LenRes harbors a truncated IRF4 that is not downregulated by lenalidomide, we targeted IRF4/MYC axis with a selective inhibitor of the bromodomain of CBP/EP300 (SGC-CBP30), which restored lenalidomide response in XG1LenRes. This strategy also appeared to be more broadly applicable as SGC-CBP30 could re-sensitize two resistant HMCLs with low but detectable CRBN expression to lenalidomide, suggesting that targeting CBP/E300 is a promising approach to restore IMiD sensitivity in MM with detectable CRBN expression.
| S-EPMC6370766 | biostudies-literature
Project description:Adult T-cell lymphoma/leukemia (ATL) is an aggressive subtype of leukemia/lymphoma caused by human T-cell leukemia virus type-1 (HTLV-1) and existing chemotherapy for ATL remains with extremely poor prognosis. Therefore, more effective therapeutic options are urgent needs for this disease. Since recent two clinical studies proved promising curability of Lenalidomide (LEN, a second-generation immunomodulatory drug [IMiDs]) for ATL patients, we investigated the direct growth-inhibitory machineries of LEN on ATL cells. Among 13 ATL-related cell lines, Hut102 and TL-Om1 exhibited best response to LEN treatment and LEN-induced functional modulation of E3-ubiquitin ligase cereblon (CRBN) induced degradation of hematopoietic-specific ikaros-family transcription factors IKZF1 and IKZF3 followed by suppression of their down-stream effectors IRF4 and c-Myc (both have been implied to promote ATL cell malignancy). Additionally, Hut102 and TL-Om1 displayed impaired expression of IKZF2 (deletion in HuT102 and altered translational variants in TL-Om1). LEN-induced growth inhibition to these two cell-lines seemed to be attributed to functional deprivation of all IKZF1/2/3. While CRBN-knockdown (KD) in HuT102 imposed LEN-resistance, IKZF2-KD in LEN-resistant ED40515 induced LEN sensitivity. DNA microarray analysis on LEN-treated HuT102 and OATL4 (LEN-resistant) displayed distinct LEN-responding transcriptional profiles; restoration of immune competency and oncogenic growth promotion respectively. Oral administration of LEN to HuT102-xenographted SCID mice demonstrated significant reduction of tumor mass. Finally, a novel form of IMiDs or cereblon modulator (CELMoD), iberdomide (IBE) exerted deeper and wider range of growth suppression to ATL cells including IKZF2 down regulation. Altogether, these findings strongly indicate the therapeutic advantages of IMiDs or CELMoD against ATL.
2024-02-15 | GSE221056 | GEO
Project description:Adult T-cell lymphoma/leukemia (ATL) is an aggressive subtype of leukemia/lymphoma caused by human T-cell leukemia virus type-1 (HTLV-1) and existing chemotherapy for ATL remains with extremely poor prognosis. Therefore, more effective therapeutic options are urgent needs for this disease. Since recent two clinical studies proved promising curability of Lenalidomide (LEN, a second-generation immunomodulatory drug [IMiDs]) for ATL patients, we investigated the direct growth-inhibitory machineries of LEN on ATL cells. Among 13 ATL-related cell lines, Hut102 and TL-Om1 exhibited best response to LEN treatment and LEN-induced functional modulation of E3-ubiquitin ligase cereblon (CRBN) induced degradation of hematopoietic-specific ikaros-family transcription factors IKZF1 and IKZF3 followed by suppression of their down-stream effectors IRF4 and c-Myc (both have been implied to promote ATL cell malignancy). Additionally, Hut102 and TL-Om1 displayed impaired expression of IKZF2 (deletion in HuT102 and altered translational variants in TL-Om1). LEN-induced growth inhibition to these two cell-lines seemed to be attributed to functional deprivation of all IKZF1/2/3. While CRBN-knockdown (KD) in HuT102 imposed LEN-resistance, IKZF2-KD in LEN-resistant ED40515 induced LEN sensitivity. DNA microarray analysis on LEN-treated HuT102 and OATL4 (LEN-resistant) displayed distinct LEN-responding transcriptional profiles; restoration of immune competency and oncogenic growth promotion respectively. Oral administration of LEN to HuT102-xenographted SCID mice demonstrated significant reduction of tumor mass. Finally, a novel form of IMiDs or cereblon modulator (CELMoD), iberdomide (IBE) exerted deeper and wider range of growth suppression to ATL cells including IKZF2 down regulation. Altogether, these findings strongly indicate the therapeutic advantages of IMiDs or CELMoD against ATL.
2024-02-15 | GSE221062 | GEO