Abstract
BackgroundImmunomodulatory 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 MethodMM and WM-derived cell lines, and Waldenström's CD19+ cells were treated using both lenalidomide and pomalidomide. Stable CRBN expressing cells were generated.ResultsWM-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.ConclusionThis 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.
Highlights
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immunomoludatory drugs, IMid compounds®, used with success in treatment of B cell malignancies such as multiple myeloma (MM) [1]
We demonstrated a modulation of the downstream targets of Interferon Regulatory Factor 4 (IRF4), despite low expression of cereblon, and hypothesized IRF4 was the cause for resistance to IMid compounds
This study demonstrated that mechanisms of resistance to IMid compounds could be not related to cereblon
Summary
Thalidomide and its derivatives, lenalidomide and pomalidomide, are immunomoludatory drugs, IMid compounds®, used with success in treatment of B cell malignancies such as multiple myeloma (MM) [1]. We hypothesized WM tumour cells might develop mechanisms of resistance to lenalidomide, and possibly across IMid compounds, hampering its effects; and sought to identify and describe these mechanisms. Toll-like receptors (TLRs) pathway, whose MYD88 is part of, is one of the main WM signaling pathways, along with and interconnected to B-cell Receptor (BCR) and Bruton’s tyrosine kinase (BTK) pathways. All of these pathways signal through a regulation of Interferon Regulatory Factor 4 (IRF4) [7]. Immunomodulatory drugs, IMid compounds, are active in Waldenström's macroglobulinemia (WM), 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
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