Role of IRF4 in resistance to immunomodulatory (IMid) compounds® in Waldenström’s macroglobulinemia
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Elisabeth Bertrand1,2,4, Nathalie Jouy1,8, Salomon Manier1,2,3,4, Guillemette Fouquet3, Stéphanie Guidez6,7, Eileen Boyle3, Stéphanie Noel7, Cécile Tomowiak6,7, Charles Herbaux3, Susanna Schraen5, Claude Preudhomme1,2,4,5, Bruno Quesnel1,2,3,4, Stéphanie Poulain1,2,4,5 and Xavier Leleu6,7
1Univ. Lille, UMR-S 1172, Factors of Persistence of Leukemic Cells Team, JPARC - Centre de Recherche Jean-Pierre AUBERT, Neurosciences et Cancer, Lille, France
2Inserm, UMR-S 1172, Factors of Persistence of Leukemic Cells Team, Lille, France
3Service des Maladies du Sang, CHU, Lille, France
4Institut pour la Recherche sur le Cancer de Lille, Factors of Persistence of Leukemic Cells Team, Lille, France
5Laboratoire d’Hématologie, Centre de Biologie et Pathologie, CHU, Lille, France
6Service d’Hématologie et Thérapie Cellulaire, Hôpital La Milétrie, et Faculté de Médecine, CHU, Poitiers, France
7CIC Inserm 1402, CHU, Poitiers, France
8Plateau de Cytométrie, BioImaging Center Lille Nord de France, BICeL Campus Hospitalo-Universitaire, Lille, France
Xavier Leleu, email: [email protected]
Keywords: Waldenström’s macroglobulinemia; IMid compounds; resistance; IRF4
Received: June 29, 2017 Accepted: November 17, 2017 Published: December 04, 2017
Background: Immunomodulatory drugs, IMid compounds, are active in Waldenström's macroglobulinemia (WM), although in a lesser extent than multiple myeloma, where it was initially developed. We hypothesized WM tumour cells might develop mechanisms of resistance, and sought to identify and describe these mechanisms.
Material and Method: MM and WM-derived cell lines, and Waldenström's CD19+ cells were treated using both lenalidomide and pomalidomide. Stable CRBN expressing cells were generated.
Results: WM-derived cells were resistant to IMid compounds. We demonstrated a modulation of the downstream targets of IRF4, despite low expression of cereblon, and hypothesized IRF4 was the cause for resistance to IMid compounds. We ruled out the role of various IRF4 regulatory mechanisms, and other pathways activating WM tumor cells, such as B cell activators.
Conclusion: This study demonstrated that mechanisms of resistance to IMid compounds could be not related to cereblon. IRF4 was identified as the potential mechanism of resistance to lenalidomide and pomalidomide in WM. It potentially explains the lesser activity observed in the clinic in WM. Interestingly, some WM patients benefited strongly to lenalidomide and pomalidomide, and future studies will have to describe the indirect mechanisms of IMid compounds in WM, possibly related to an immune-mediated process.
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