IMiD immunomodulatory compounds block C/EBPβ translation through eIF4E down-regulation resulting in inhibition of MM

Immunomodulatory derivatives of thalidomide (IMiD compounds), such as pomalidomide and lenalidomide, are highly active in multiple myeloma (MM) treatment. However, the precise mechanisms of action and resistance in MM are unresolved. Here we show that IMiD compounds down-regulate CCAAT/enhancer-binding protein-beta (C/EBP beta) resulting in abrogation of cell proliferation. Overexpression of C/EBP beta rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBP beta is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBP beta protein led to impaired transcription of interferon regulatory factor 4 (IRF4). Down-regulation of IRF4 by lenalidomide was confirmed by longitudinal studies of bone marrow samples from 23 patients obtained before and during lenalidomide treatment using CD138(+)/IRF4(+) double labeling. In contrast to down-regulation of C/EBP beta protein, IMiD compounds did not alter C/EBP beta mRNA levels or protein stability, suggesting translational regulation of C/EBP beta. We could demonstrate that C/EBP beta protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBP beta axis by IMiD compounds was not observed in IMiD-resistant MM cells. However, targeting translation at a different level by inhibiting eukaryotic translation initiation factor 4E-binding protein 1 phosphorylation overcame resistance, suggesting that this pathway is critical and might be a target to overcome drug resistance. (Blood. 2011; 117(19): 5157-5165)