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Project description:Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM.
| S-EPMC8870223 | biostudies-literature
Project description:Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in transcriptome and develop de novo drug resistance. As a critical component in transcriptional regulation, how chromatin landscape is transformed in MM cells and regulates the transcriptional response to BMSCs remains elusive. We profiled transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells coexisting with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with accessibility increased at multiple regulatory sites were preferentially induced by BMSCs and enriched in response to drug and unfavorable prognostic markers from several MM patient cohorts. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulated the BMSC-induced transformation of regulome linked to the response to external stimuli. Together, we characterized BMSC-induced transcriptome and regulome signatures of MM cells and prioritized TFs for future study to depict epigenetic mechanisms of BMSC-induced drug resistance in MM.
2022-02-16 | GSE193657 | GEO
Project description:Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in transcriptome and develop de novo drug resistance. As a critical component in transcriptional regulation, how chromatin landscape is transformed in MM cells and regulates the transcriptional response to BMSCs remains elusive. We profiled transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells coexisting with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with accessibility increased at multiple regulatory sites were preferentially induced by BMSCs and enriched in response to drug and unfavorable prognostic markers from several MM patient cohorts. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulated the BMSC-induced transformation of regulome linked to the response to external stimuli. Together, we characterized BMSC-induced transcriptome and regulome signatures of MM cells and prioritized TFs for future study to depict epigenetic mechanisms of BMSC-induced drug resistance in MM.
2022-02-16 | GSE193656 | GEO
Project description:Bone Marrow Stroma-induced Transcriptome and Regulome Signatures of Multiple Myeloma
| PRJNA797082 | ENA
Project description:Bone Marrow Stroma-induced Transcriptome and Regulome Signatures of Multiple Myeloma [RNA-seq]
| PRJNA797085 | ENA
Project description:Bone Marrow Stroma-induced Transcriptome and Regulome Signatures of Multiple Myeloma [ATAC-seq]
| PRJNA797084 | ENA
Project description:Multiple myeloma is a B-cell lineage cancer in which neoplastic plasma cells expand in the bone marrow and pathophysiological interactions with components of microenvironment influence many biological aspects of the malignant phenotype, including apoptosis, survival, proliferation, and invasion. Despite the therapeutic progress achieved in the last two decades with the introduction of a more effective and safe new class of drugs (i.e., immunomodulators, proteasome inhibitors, monoclonal antibodies), there is improvement in patient survival, and multiple myeloma (MM) remains a non-curable disease. The bone marrow microenvironment is a complex structure composed of cells, extracellular matrix (ECM) proteins, and cytokines, in which tumor plasma cells home and expand. The role of the bone marrow (BM) microenvironment is fundamental during MM disease progression because modification induced by tumor plasma cells is crucial for composing a "permissive" environment that supports MM plasma cells proliferation, migration, survival, and drug resistance. The "activated phenotype" of the microenvironment of multiple myeloma is functional to plasma cell proliferation and spreading and to plasma cell drug resistance. Plasma cell drug resistance induced by bone marrow stromal cells is mediated by stress-managing pathways, autophagy, transcriptional rewiring, and non-coding RNAs dysregulation. These processes represent novel targets for the ever-increasing anti-MM therapeutic armamentarium.
| S-EPMC7013615 | biostudies-literature
Project description:Background:Multiple myeloma is a plasma cell dyscrasia characterized by transformation of B cells into malignant cells. Although there are data regarding the molecular pathology of multiple myeloma, the molecular mechanisms of the disease have not been fully elucidated. Aims:To investigate the gene expression profiles in bone marrow myeloma cells via RNA-sequencing technology. Study Design:Cell study. Methods:Myeloma cells from four patients with untreated multiple myeloma and B cells from the bone marrow of four healthy donors were sorted using a FACSAria II flow cytometer. The patient pool of myeloma cells and the control pool of B cells were the two comparative groups. A transcriptome analysis was performed and the results were analyzed using bioinformatics tools. Results:In total, 18.806 transcripts (94.4%) were detected in the pooled multiple myeloma patient cells. A total of 992 regions were detected as new exon candidates or alternative splicing regions. In addition, 490 mutations (deletions or insertions), 1.397 single nucleotide variations, 415 fusion transcripts, 132 frameshift mutations, and 983 fusions, which were reported before in the National Center for Biotechnology Information, were detected with unknown functions in patients. A total of 35.268 transcripts were obtained (71%) (25.355 transcripts were defined previously) in the control pool. In this preliminary study, the first 50 genes were analyzed with the MSigDB, Enrichr, and Panther gene set enrichment analysis programs. The molecular functions, cellular components, pathways, and biological processes of the genes were obtained and statistical values were determined using bioinformatics tools and are presented as a supplemental file. Conclusion:EEF1G, ITM2C, FTL, CLPTM1L, and CYBA are identified as possible candidate genes associated with myelomagenesis.
| S-EPMC6335938 | biostudies-literature
Project description:BACKGROUND:Multiple myeloma (MM) cells gain protection against drugs through interaction with bone marrow stromal cells (BMSCs). This form of resistance largely accounts for resistance to therapy in MM patients which warrants further exploration to identify more potential therapeutic targets. METHODS:We performed miRNA/mRNA qPCR arrays and western blotting to analyze transcriptional and translational changes in MM cells co-cultured with BMSCs. Drug cytotoxicity and apoptosis in MMGFP-BMSC co-cultures were measured using fluorescence plate reader and flowcytometry, respectively. miRNA was overexpressed in MM cell lines using Lentiviral transduction, miRNA-3'UTR binding was examined using luciferase assay. RESULTS:We found that BMSCs downregulated miR-101-3p and upregulated survivin (BIRC5) in MM cells. Survivin was downregulated by miR-101-3p overexpression and found to be a direct target of miR-101-3p using 3'UTR luciferase assay. Overexpression of survivin increased viability of MM cells in the presence of anti-myeloma drugs, and miR-101-3p inhibition by anti-miR against miR-101-3p upregulated survivin. Furthermore, overexpression of miR-101-3p or silencing of survivin triggered apoptosis in MM cells and sensitized them to anti-myeloma drugs in the presence of BMSCs overcoming the stroma-induced drug resistance. CONCLUSIONS:Our study demonstrates that BMSC-induced resistance to drugs is associated with survivin upregulation which is a direct target of miR-101-3p. This study also identifies miR-101-3p-survivin interaction as a druggable target involved in stroma-mediated drug resistance in MM and suggests it for developing more efficient therapeutic strategies.
| S-EPMC6805455 | biostudies-literature
Project description:Despite evidence about the implication of the bone marrow (BM) stromal microenvironment in multiple myeloma (MM) cell growth and survival, little is known about the effects of myelomatous cells on BM stromal cells. Mesenchymal stromal cells (MSCs) from healthy donors (dMSCs) or myeloma patients (pMSCs) were co-cultured with the myeloma cell line MM.1S, and the transcriptomic profile of MSCs induced by this interaction was analyzed. Deregulated genes after co-culture common to both d/pMSCs revealed functional involvement in tumor microenvironment cross-talk, myeloma growth induction and drug resistance, angiogenesis and signals for osteoclast activation and osteoblast inhibition. Additional genes induced by co-culture were exclusively deregulated in pMSCs and predominantly associated to RNA processing, the ubiquitine-proteasome pathway, cell cycle regulation, cellular stress and non-canonical Wnt signaling. The upregulated expression of five genes after co-culture (CXCL1, CXCL5 and CXCL6 in d/pMSCs, and Neuregulin 3 and Norrie disease protein exclusively in pMSCs) was confirmed, and functional in vitro assays revealed putative roles in MM pathophysiology. The transcriptomic profile of pMSCs co-cultured with myeloma cells may better reflect that of MSCs in the BM of myeloma patients, and provides new molecular insights to the contribution of these cells to MM pathophysiology and to myeloma bone disease.
| S-EPMC4226683 | biostudies-literature