Lenalidomide downregulates the cell survival factor, interferon regulatory factor‐4, providing a potential mechanistic link for predicting response

Abstract

SummaryOverexpression of the transcription factor interferon regulatory factor-4 (IRF4), which is common in multiple myeloma (MM), is associated with poor prognosis. Patients with higher IRF4 expression have significantly poorer overall survival than those with low IRF4 expression. Lenalidomide is an IMiD Ò immunomodulatory compound that has both tumouricidal and immunomodulatory activity in MM. This study showed that lenalidomide downregulated IRF4 levels in MM cell lines and bone marrow samples within 8 h of drug exposure. This was associated with a decrease in MYC levels, as well as an initial G1 cell cycle arrest, decreased cell proliferation, and cell death by day 5 of treatment. In eight MM cell lines, high IRF4 levels correlated with increased lenalidomide sensitivity. The clinical significance of this observation was investigated in 154 patients with MM. Among MM patients with high levels of IRF4 expression, treatment with lenalidomide led to a significantly longer overall survival than other therapies in a retrospective analysis. These data confirm the central role of IRF4 in MM pathogenesis; indicate that this is an important mechanism by which lenalidomide exerts its antitumour effects; and may provide a mechanistic biomarker to predict response to lenalidomide.

Cereblon expression is required for the antimyeloma activity of lenalidomide and pomalidomide

“…Recent studies demonstrated that high IRF4 levels correlated with increased lenalidomide sensitivity. 17,18 Another study demonstrated that activation of the Wnt/␤-catenin pathway mediates lenalidomide resistance in MM. 15 In a study performed on Del(5q) myelodysplastic syndrome, the secondary resistance to lenalidomide was found to be associated with CDC25C and PP2A overexpression.…”

Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma

“…Drug-induced downstream effects of altered CRBN activity include cell-cycle arrest with upregulation of the cyclin-dependent kinase inhibitor p21 and downregulation of interferon regulatory factor 4 (IRF4), a MM cell survival factor that targets critical genes including MYC, CDK6, and CASP. [6][7][8] Collateral effects on immune function including inhibition of tumor necrosis factor and upregulation of interleukin 2, T lymphocytes, and natural killer cells are also documented.…”

Elevated Translation Initiation Factor eIF4E Is an Attractive Therapeutic Target in Multiple Myeloma

“…IRF4 was identified as an oncogene associated with the chromosomal translocation t(6;14) (p25;q32) (37) controlling multiple myeloma survival (31), and overexpression of IRF4 is an adverse prognostic survival marker (31,38). IRF4 is a target of lenalidomide in multiple myeloma (23,39). Interestingly, in myeloma, IRF4 and c-MYC mutually reinforce the expression of each other (31).…”