Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells
Theresa Jakobsen1, Mette Dahl2,3, Konstantinos Dimopoulos2,3
1Department of Biomedicine, Aarhus University, Høegh-Guldbergs Gade 10, DK-8000 Aarhus, Denmark.
Abstract:
Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, may induce significant remissions in multiple myeloma (MM) patients, but relapses are frequently observed and the underlying molecular mechanisms for this are not completely understood. Circular RNAs (circRNAs) constitute an emerging class of non-coding RNAs with important roles in cancer. Here, we profiled genome-wide expression patterns of circRNAs in IMiD-sensitive MM cells and their resistant counterparts as well as in IMiD-resistant cells treated with specific epigenetic drugs alone or in combination. We found that genome-wide circRNA expression patterns reflect IMiD sensitivity and ciRS-7 (also known as CDR1as) was the most downregulated circRNA upon acquired resistance. The depletion of ciRS-7 correlated with increased methylation levels of the promoter CpG island of its host gene, LINC00632. Expression of LINC00632 and ciRS-7 was partly restored by treatment with a combination of an EZH2 inhibitor (EPZ-6438) and a DNA methyl transferase inhibitor (5-azacytidine), which also restores the IMiD sensitivity of the cells. However, knockdown of ciRS-7 did not affect IMiD sensitivity and we found that ciRS-7 also becomes epigenetically silenced after prolonged cell culture without drug-exposure. In conclusion, we found that genome-wide circRNA expression patterns reflect IMiD sensitivity in an in vitro model of acquired resistance.
Insights
Circular RNAs (circRNAs) reflect drug sensitivity in multiple myeloma (MM). Acquired resistance to immunomodulatory drugs (IMiDs) involves downregulation of ciRS-7, linked to epigenetic silencing.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Immunomodulatory drugs (IMiDs) like lenalidomide and pomalidomide are effective against multiple myeloma (MM), but drug resistance limits their long-term efficacy.
- The molecular mechanisms underlying IMiD resistance in MM are not fully understood.
- Circular RNAs (circRNAs) are a class of non-coding RNAs with emerging roles in cancer development and progression.
Purpose of the Study:
- To investigate genome-wide circRNA expression patterns in IMiD-sensitive and IMiD-resistant multiple myeloma (MM) cells.
- To identify specific circRNAs associated with acquired resistance to IMiDs.
- To explore the potential of epigenetic drugs in overcoming IMiD resistance by modulating circRNA expression.
Main Methods:
- Profiling of genome-wide circRNA expression in IMiD-sensitive and resistant MM cell lines.
- Analysis of circRNA expression in resistant cells treated with epigenetic drugs (EZH2 inhibitor and DNA methyltransferase inhibitor).
- Investigation of the correlation between circRNA depletion, host gene methylation, and IMiD sensitivity.
Main Results:
- Genome-wide circRNA expression patterns differentiated IMiD-sensitive and resistant MM cells.
- ciRS-7 (CDR1as) was significantly downregulated in IMiD-resistant MM cells.
- Depletion of ciRS-7 correlated with increased promoter methylation of its host gene, LINC00632.
- Combination epigenetic therapy partially restored LINC00632 and ciRS-7 expression and resensitized cells to IMiDs.
- ciRS-7 knockdown alone did not impact IMiD sensitivity, and ciRS-7 silencing occurred even without drug exposure.
Conclusions:
- Genome-wide circRNA expression patterns can serve as biomarkers for IMiD sensitivity in multiple myeloma.
- Acquired resistance to IMiDs in MM is associated with epigenetic silencing of specific circRNAs, such as ciRS-7.
- Epigenetic modulation offers a potential strategy to overcome IMiD resistance in multiple myeloma.
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