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An Organotypic High Throughput System for Characterization of Drug Sensitivity of Primary Multiple Myeloma Cells
Published on: July 15, 2015
Identification of genes regulated by dexamethasone in multiple myeloma cells using oligonucleotide arrays
Dharminder Chauhan1, Daniel Auclair, Elisabeth K Robinson
1The Jerome Lipper Multiple Myeloma Center, Department of Adult Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, MA 02115, USA.
Abstract:
Our previous studies have characterized Dexamethasone (Dex)-induced apoptotic signaling pathways in multiple myeloma (MM) cells; however, related transcriptional events are not fully defined. In the present study, gene expression profiles of Dex-treated MM cells were determined using oligonucleotide arrays. Dex triggers early transient induction of many genes involved in cell defense/repair-machinery. This is followed by induction of genes known to mediate cell death and repression of growth/survival-related genes. The molecular and genetic alterations associated with Dex resistance in MM cells are also unknown. We compared the gene expression profiles of Dex-sensitive and Dex-resistant MM cells and identified a number of genes which may confer Dex-resistance. Finally, gene profiling of freshly isolated MM patient cells validates our in vitro MM cell line data, confirming an in vivo relevance of these studies. Collectively, these findings provide insights into the basic mechanisms of Dex activity against MM, as well as mechanisms of Dex-resistance in MM cells. These studies may therefore allow improved therapeutic uses of Dex, based upon targeting genes that regulate MM cell growth and survival.
Insights
Dexamethasone (Dex) impacts multiple myeloma (MM) cell gene expression, initiating defense responses before triggering cell death. Gene profiling reveals mechanisms of Dex resistance in MM, aiding potential therapeutic strategies.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Dexamethasone (Dex) is a corticosteroid used in multiple myeloma (MM) treatment.
- While Dex-induced apoptosis in MM cells is known, the associated transcriptional changes remain incompletely understood.
- Mechanisms underlying Dex resistance in MM are also largely undefined.
Purpose of the Study:
- To define the transcriptional events associated with Dexamethasone treatment in multiple myeloma cells.
- To identify genetic alterations contributing to Dexamethasone resistance in MM.
- To explore the in vivo relevance of observed gene expression changes.
Main Methods:
- Gene expression profiling of Dexamethasone-treated MM cell lines using oligonucleotide arrays.
- Comparison of gene expression profiles between Dexamethasone-sensitive and Dexamethasone-resistant MM cells.
- Gene profiling of freshly isolated MM patient cells.
Main Results:
- Dexamethasone induced early, transient expression of cell defense/repair genes.
- Subsequent induction of cell death genes and repression of growth/survival genes were observed.
- Specific genes potentially conferring Dexamethasone resistance were identified by comparing sensitive and resistant MM cells.
- In vitro findings were validated in freshly isolated patient MM cells.
Conclusions:
- Gene expression profiling provides insights into Dexamethasone's mechanism of action against MM.
- Identified genes offer potential targets for overcoming Dexamethasone resistance.
- Findings support the development of improved therapeutic strategies for MM by targeting genes regulating MM cell growth and survival.
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