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Simple Summary  Multiple myeloma (MM) constitutes the second most common hematological malignancy and is caused by aberrant plasma cell proliferation in the bone marrow. While recent improvements in the treatment of MM has been observed using immunomodulatory drugs (IMiDs), patients often relapse due to acquired drug resistance and no cure for the disease is currently available. In this report, we profile circular RNA (circRNA) expression patterns in cultured MM cells being sensitive to IMiDs and their resistant counterparts. CircRNAs constitute a large class of non-coding RNA molecules with emerging roles in cancer development and progression, but have not previously been explored in this context. We found that global circRNA expression patterns reflect IMiD sensitivity, but the most downregulated circRNA in IMiD resistant MM cells did not seem to be a direct driver of IMiD resistance. Future studies should investigate other circRNA candidates identified here in the context of IMiD resistance.    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.

Genome-Wide Circular RNA Expression Patterns Reflect Resistance to Immunomodulatory Drugs in Multiple Myeloma Cells