Cereblon enhancer methylation and IMiD resistance in multiple myeloma

Author:

Haertle Larissa12ORCID,Barrio Santiago134,Munawar Umair1ORCID,Han Seungbin1ORCID,Zhou Xiang1,Vogt Cornelia1,Fernández Rafael Alonso4,Bittrich Max1ORCID,Ruiz-Heredia Yanira34,Da Viá Matteo156ORCID,Zovko Josip1,Garitano-Trojaola Andoni1,Bolli Niccolò56,Ruckdeschel Anna1,Stühmer Thorsten1,Chatterjee Manik1,Kull Miriam7,Krönke Jan7ORCID,Agirre Xabier8,Martin-Subero Jose I.910,Raab Peter11,Einsele Hermann1,Rasche Leo1ORCID,Martinez-Lopez Joaquin34,Haaf Thomas2ORCID,Kortüm K. Martin1ORCID

Affiliation:

1. Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany;

2. Institute of Human Genetics, Julius Maximilian University of Würzburg, Würzburg, Germany;

3. Altum Sequencing Co., Madrid, Spain;

4. Department of Hematology, Hospital Universitario 12 de Octubre, Spanish National Cancer Research Center, Complutense University Madrid, Madrid, Spain;

5. Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy;

6. Hematology Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy;

7. Department of Internal Medicine III, University Hospital Ulm, Ulm, Germany;

8. Área de Hemato-Oncología, Centro de Investigación Médica Aplicada, Centro de Investigación Biomédica en Red-Cáncer (CIBERONC), Instituto de Investigación Sanitaria de Navarra, Universidad de Navarra, Pamplona, Spain;

9. Biomedical Epigenomics Group, Institut d’Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Barcelona, Spain;

10. Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain; and

11. Department of Orthopaedic Surgery, König Ludwig Haus, University of Würzburg, Würzburg, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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