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Cereblon Enhancer Methylation and IMiD Resistance in Multiple Myeloma.

Cereblon is the direct binding target of the immunomodulatory drugs that are commonly used to treat Multiple Myeloma, the second most frequent hematologic malignancy. Patients respond well to initial IMiD treatment but virtually all develop drug resistance over time with the underlying mechanisms poorly understood. We identified a yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found increased in healthy plasma cells, but more pronounced in IMiD refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNTMi in vitro experiments induced CRBN enhancer demethylation and sensitizing effects on Lenalidomide treatment were observed in two MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in Multiple Myeloma and may predict IMiD response prior treatment.