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Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [RNA-seq]

ABSTRACT: Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [RNA-seq]

PROVIDER: PRJNA1133724 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29760471_1.fastq.gz	Fastqsanger.gz
	SRR29760471_2.fastq.gz	Fastqsanger.gz
	SRR29760472_1.fastq.gz	Fastqsanger.gz
	SRR29760472_2.fastq.gz	Fastqsanger.gz
	SRR29760473_1.fastq.gz	Fastqsanger.gz

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Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [ATAC-seq]

Project description:Multiple Myeloma is the second most hematological cancer. RUVBL1 and RUVBL2 forms a subcomplex of many chromatin remodeling complexes implicated in cancer progress. As an inhibitor specific to the RUVBL1/2 complex, CB-6644 exhibits remarkable anti-tumor activity in xenograft models of Burkitt’s lymphoma and multiple myeloma (MM). In this work, we defined transcriptional signatures corresponding to CB-6644 treatment in MM cells and determined underlying epigenetic changes in terms of chromatin accessibility.CB-6644 upregulated biological processes related to interferon response and downregulated those linked to cell proliferation in MM cells. Transcriptional regulator inference identified ATF4/CEBP and E2Fs as regulators for downregulated genes and MED1 and MYC as regulators for upregulated genes. CB-6644-induced changes in chromatin accessibility occurred mostly in non-promoter regions. Footprinting analysis identified transcription factors implied in modulating chromatin accessibility in response to CB-6644 treatment, including ATF4/CEBP and IRF4. Lastly, integrative analysis of transcription responses to various chemical compounds of the molecular signature genes from public gene expression data identified CB-5083, a p97 inhibitor, as a synergistic candidate with CB66-44 in MM cells, but experimental validation refuted this hypothesis.

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Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [RNA-seq]

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Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [ATAC-seq]

Project description:Molecular Signatures of CB-6644 inhibition of the RUVBL1/2 complex in Multiple Myeloma [ATAC-seq]

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Gene expression profile of multiple myeloma cell lines treated with CB-5083

Project description:The goal was to determine the gene expression differences between CB-5083 and Bortezomib treated multiple myeloma cell lines Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system (UPS) and CB-5083, a first in class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematological and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma (MM) cell lines and a number of in vivo MM models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response (UPR) and apoptosis. CB-5083 decreases viability in MM cell lines and patient derived MM cells, including those with background proteasome inhibitor (PI) resistance. CB-5083 has a unique mechanism of action that combines well with PIs which is likely owing to the p97-dependent retro-translocation of the transcription factor, Nrf1, which transcribes proteasome subunit genes following exposure to a PI. In vivo studies using clinically relevant MM models demonstrate that single-agent CB-5083 inhibits tumor growth and combines well with MM standard of care agents. Our preclinical data demonstrate the efficacy of CB-5083 in several MM disease models and provide the rationale for clinical evaluation as monotherapy and in combination in MM.

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RUVBL1 and RUVBL2 as novel druggable DNA Damage Response regulators in the MYCN regulatory network in neuroblastoma

Project description:To understand its role RUVBL1/2 in neuroblastoma, we inhibited RUVBL1/2 ATPase activity two independent cell lines, SK-N-AS and CBL-BA, with 250 nM CB-6644 at 0, 24, 48, and 72 hrs and performed RNA sequencing.

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Project description:Gene expression signatures in multiple myeloma

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miRNA expression signatures in multiple myeloma

Project description:miRNA expression signatures in multiple myeloma

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Project description:In the present study, the gene expression profiling was carried out to identify the gene targets affected by miRNAs deregulated in multiple myeloma. A gene expression signature was generated for 45 patients of multiple myeloma as compared to controls (Pooled from 10 Hodgkin's disease samples).

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Project description:miRNA profiling in multiple myeloma - microRNAs represent a class of noncoding regulators of gene expression implicated in several biological and pathophysiological processes, including cancer. We investigate here their role in multiple myeloma using miChip-arrays interrogating 559 miRNAs in 92 purified myeloma-, MGUS-, normal plasma cell- and myeloma cell line samples. Impact on gene expression is assessed by Affymetrix U133 2.0 DNA-microarrays in 741 samples including two cohorts of 332 and 345 myeloma patients; chromosomal aberrations are assessed by iFISH, survival for 247 and 345 patients undergoing up-front high-dose therapy and autologous stem cell transplantation. Compared to normal plasma cells, 67/559 (12%) miRNAs are differentially expressed with fold changes of 4.6 to -3.1 in myeloma-, 20 (3.6%) in MGUS-samples, and three (0.5%) between MGUS- and myeloma-samples. Expression of miRNAs is associated with biological and pathophysiological parameters, i.e. proliferation, chromosomal aberrations, e.g. t(4;14), tumor mass, and gene expression-based high-risk scores. This holds true for target-gene signatures of regulated mRNAs. miRNA-expression confers prognostic significance for event-free (72/559) and overall survival (69/559), as do respective target-gene signatures. In conclusion, the miRNome of myeloma confers a pattern of small changes of individual miRNAs compared to normal plasma cells impacting on gene expression, biological functions, and survival.

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Multiple myeloma

Project description:Multiple myeloma

| PRJNA515992 | ENA