Ontology highlight
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PROVIDER: PRJNA1095389 | ENA |
REPOSITORIES: ENA
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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:Advancements in the treatment of multiple myeloma (MM) have resulted in significant improvement in the survival rate for patients <65, however not for patients >65. There is a particular need for improved therapies for this patient population. The protein arginine methyltransferase, CARM1 (coactivator associated arginine methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors have been developed. MM cell lines are particularly dependent on CARM1 for cell survival. Here, we show that CARM1 targeting through a small molecule drug potentiates immunomodulatory drugs (IMiD) treatment in models of MM, likely through synergistic targeting of Aiolos (IKZF3) and MYC expression. Consistent with this, biorational development of a new molecule, 074, comprised of the CARM1 inhibitor, EZM2302, linked to the IMiD pomalidomide led to more potent killing of MM cells than either compound individually. 074 treatment or the combination of CARM1 knockdown (KD) with pomalidomide led to an upregulation of inflammation and interferon signaling pathways and downregulation of MYC signaling. Importantly, 074 reversed IMiD resistance characterized by MYC protein upregulation and cereblon (CRBN) protein downregulation. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease.
2025-05-06 | PXD046700 | Pride
Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. A total of 13 ChIP-seq samples were sequenced. Samples were treated with control (DMSO) or test compound (2.5 uM SGC-CBP30 or 0.25uM CPI267203) for 6 hours. Signal from input samples was included to subtract background signal from each ChIP-seq sample. Antibodies used were against p300, H3K18ac, H3K27ac, or BRD4.
2016-01-05 | E-GEOD-71909 | biostudies-arrayexpress
Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE197486 | GEO
Project description:Bromodomain-containing protein 9 (BRD9) has emerged as a promising therapeutic target for blood cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). PROTAC-based BRD9 degraders effectively hamper the growth and survival of leukemia cells; however, the underlying mechanism of these BRD9 degraders remains unclear. In this study, we demonstrated that depletion of BRD9 triggers DNA damage via R-loop accumulation, leading to conflicts between transcription and replication processes. Replication stress inhibits the proliferation of leukemia cells and promotes their differentiation. Mechanistically, BRD9 plays a pivotal role in recruiting BRD2 and BRD4 to chromatin through direct interactions, which is critical for preventing R-loop formation during transcription. Depletion of BRD9 in leukemia cells reduces the occupancy of BRD2 and BRD4 at R-loop-prone sites, thus promoting R-loop accumulation, transcription-replication collision, excessive DNA damage, and ultimately, the demise of cancer cells. These findings provide valuable insights into the mechanisms by which BRD9 degraders function as effective therapies for leukemia mediated by the pathological accumulation of R-loops.
2025-07-16 | GSE300622 | GEO
Project description:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network. Through the use of CBP/EP300 bromodomain inhibitors (CBP/EP300i), we demonstrate that MYC expression in BETi-resistant cells is dependent on CBP/EP300 bromodomains and that treatment with CBP/EP300i restores phenotypic sensitivity.
2016-01-05 | E-GEOD-64317 | biostudies-arrayexpress
Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.
2023-02-08 | GSE197487 | GEO
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:Pharmacological inhibition of chromatin co-regulatory factors represents a clinically validated strategy to modulate oncogenic signaling through selective attenuation of gene expression. Here, we demonstrate that CBP/EP300 bromodomain inhibition preferentially abrogates the viability of multiple myeloma cell lines. Phenotypic effects are preceded by the direct transcriptional suppression of the lymphocyte-specific transcription factor IRF4 and the subsequent down-regulation of the IRF4 transcriptional program. Ectopic expression of IRF4 antagonizes the phenotypic effects of CBP/EP300 bromodomain inhibition and prevents the suppression of the IRF4 target c-MYC. These findings suggest that CBP/EP300 bromodomain inhibition represents a viable therapeutic strategy for targeting multiple myeloma and other lymphoid malignancies dependent on the IRF4 network.
2016-01-05 | GSE71909 | GEO
Project description:Therapeutic Targeting of Protein Disulfide Isomerase PDIA1 in Multiple Myeloma
| PRJNA702993 | ENA