| Literature DB >> 34115836 |
Larissa Haertle1,2, Santiago Barrio1,3,4, Umair Munawar1, Seungbin Han1, Xiang Zhou1, Cornelia Vogt1, Rafael Alonso Fernández4, Max Bittrich1, Yanira Ruiz-Heredia3,4, Matteo Da Viá1,5,6, Josip Zovko1, Andoni Garitano-Trojaola1, Niccolò Bolli5,6, Anna Ruckdeschel1, Thorsten Stühmer1, Manik Chatterjee1, Miriam Kull7, Jan Krönke7, Xabier Agirre8, Jose I Martin-Subero9,10, Peter Raab11, Hermann Einsele1, Leo Rasche1, Joaquin Martinez-Lopez3,4, Thomas Haaf2, K Martin Kortüm1.
Abstract
Cereblon is the direct binding target of the immunomodulatory drugs (IMiDs) that are commonly used to treat multiple myeloma (MM), the second most frequent hematologic malignancy. Patients respond well to initial treatment with IMiDs, but virtually all patients develop drug resistance over time, and the underlying mechanisms are poorly understood. We identified an as yet undescribed DNA hypermethylation in an active intronic CRBN enhancer. Differential hypermethylation in this region was found to be increased in healthy plasma cells, but was more pronounced in IMiD-refractory MM. Methylation significantly correlated with decreased CRBN expression levels. DNA methyltransferase inhibitor (DNTMi) in vitro experiments induced CRBN enhancer demethylation, and sensitizing effects on lenalidomide treatment were observed in 2 MM cell lines. Thus, we provide first evidence that aberrant CRBN DNA methylation is a novel mechanism of IMiD resistance in MM and may predict IMiD response prior to treatment.Entities:
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Year: 2021 PMID： 34115836 PMCID： PMC8569411 DOI： 10.1182/blood.2020010452
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 22.113