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

Department of Medicine, Division of Hematology/Oncology, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(19):5157-65. DOI: 10.1182/blood-2010-10-314278
Source: PubMed


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-β (C/EBPβ) resulting in abrogation of cell proliferation. Overexpression of C/EBPβ rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPβ is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPβ 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/EBPβ protein, IMiD compounds did not alter C/EBPβ mRNA levels or protein stability, suggesting translational regulation of C/EBPβ. We could demonstrate that C/EBPβ protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPβ 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.

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    • "The controversial sedative, thalidomide, has immunomodulatory actions that are mediated, in large part, by lowering the rate of TNF synthesis [106, 107]. Recent analogs that more effectively achieve this include 3,6′-dithiothalidomide (3,6′-DT) [108], which readily enters the brain [109] and suppresses TNF synthesis post-transcriptionally at the level of translational regulation via the 3′-untranslated region of its messenger RNA (mRNA) [108, 110] as well as through down-regulation of the eukaryotic elongation initiation factor (eIF)-4E [111] to allow its rapid degradation. "
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    • "This complex regulates DNA repair, replication and transcription, and its inhibition by thalidomide causes teratogenic effects by preventing degradation of proteins that play a crucial role in embryonic limb development (e.g. down regulation of fibroblast growth factor 8) [4]. Drug-induced downstream effects of CRBN inhibition include cell cycle arrest with up regulation of the cyclin-dependent kinase inhibitor p21 WAF-1 [5] and down regulation of interferon regulatory factor 4 (IRF4), a MM cell survival factor that targets critical genes like MYC, CDK6 and CASP3 [6] [7] [8]. "
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    • "Lenalidomide causes concentration-dependent cell cycle arrest in G0-G1 phase by upregulating the CDK inhibitor p21 waf-1, a key cell cycle regulator that modulates the activity of CDKs, and down-regulating the activities of the prosurvival kinases ERK1/2 and Akt (17,18). Lenalidomide inhibits the translation of C/EBPβ by downregulating eIF4E, and IRF4 downregulation has been reported to be a critical factor controlling multiple myeloma survival and as a prognostic marker in patients with multiple myeloma associated with poor survival (19,20). In NSCLC, objective responses have been observed with lenalidomide-based therapy, suggesting that lenalidomide is a potent drug for NSCLC treatment. "
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