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

Abstract

IntroductionImmunomodulatory derivatives of thalidomide (IMiD compounds), such as lenalidomide and pomalidomide, represent a novel class of agents with potent activity against multiple myeloma (MM). 1,2 IMiD compounds were shown to induce antitumor, antiangiogenic, and anti-inflammatory effects. However, the precise mechanisms by which IMiD compounds induce the direct anti-MM effect have not been determined. 3 Escoubet-Lozach et al demonstrated that IMiD compounds induced G 0 -G 1 growth arrest in MM cells because of increased p21WAF-1 mRNA and protein expression through a histone demethylase LSD1-mediated epigenetic mechanism. 4 Other tumor suppressor genes, such as the early growth response genes (Egr 1-3) and cyclin-dependent kinase inhibitors (p15, p27), are also induced by lenalidomide alone and synergistically when used in combination with dexamethasone in MM cells. 5 The recent work by Xu et al showed that modulation of guanosine triphosphatase activity resulting in alteration of the cytoskeleton is another mechanism by which IMiD compounds regulate the interplay between tumor cells, their environment, and host immune cells. 6 In this study, we focused on the direct effects of IMiD compounds on MM cells and on genes critical for the pathogenesis and drug resistance of MM.CCAAT/enhancer-binding proteins (C/EBPs) belong to a large family of leucine zipper transcription factors (TFs) termed bZip proteins, which have a basic DNA-binding domain linked to a leucine zipper dimerization motif. 7 C/EBP␤ is widely expressed and exists in 3 distinct isoforms: termed LAP* (full-length protein), LAP (contains a 21-amino acid truncation at the N terminus), and LIP (contains a large N-terminal truncation and can act as a dominant-negative). 8 The C/EBP␤ isoforms are generated by alternative initiation of protein translation from a single mRNA transcript. C/EBP␤, also called NF-IL6, regulates a variety of genes involved in diverse functions, such as cellular differentiation processes, including adipogenesis, 9 cell survival, 10 tumor invasiveness, 11 and hematopoiesis. 12 Deletion of the C/EBP␤ gene in mice results in impaired generation of B lymphocytes, 13 and it has been shown that C/EBP␤ contributes to the induction of the antiapoptotic protein, BCL2, in t(14;18) lymphoma cells. 10 Earlier studies identified C/EBP␤ as a regulator of IL-6 and demonstrated that C/EBP␤ itself is also induced by IL-6, 14 the most important survival factor for MM cells. Recently, we have shown that C/EBP␤ regulates IRF4 gene expression in MM. 15 Our studies showed that down-regulation of IRF4 by C/EBP␤ further decreased expression of the TFs XBP1 and B-lymphocyte-induced maturation protein (BLIMP1). These TFs have been shown to be critical for the pathogenesis of MM. 16 Further, IRF4 participates in the immune response resulting in lymphocyte activation and generation of immunoglobulin-secreting plasma cells, and has been reported to be required for myeloma cell survival. [16][17][18][19] Previous studies reported that translational regul...

Stk40 represses adipogenesis through translational control of CCAAT/enhancer-binding proteins

“…Our data support the notion that Stk40 represses the translation of at least three members of the C/EBP family, including α, β and δ. Translation of C/EBPβ has been shown to be dependent on eIF4E activity, either in an isoform-selective fashion through different translation initiation sites Pause et al, 1994) or in an isoform nonselective manner (Li et al, 2011). Our results suggest that Stk40 controlled translation of C/EBPβ without an isoform preference, as levels of all three C/EBPβ isoforms altered when Stk40 was deleted.…”

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.…”

IMiD compounds affect CD34+ cell fate and maturation via CRBN-induced IKZF1 degradation

“…23 The following primer pairs were used: human CRBN, forward (59-TCCCGAATGTGTGTTGCCTT-39) and reverse (59-CCAGCGAGGCCATGAAGTTA-39); human PU.1, forward (59-CAAGCTTCGTGGAACTCTCC-39) and reverse (59-ACTGACAATCAGGCGCTTCT-39); and human b-actin, forward (59-CGAGCACAGAGCCTCGCCTTTG-39) and reverse (59-CGACGAGCGCGGCGATATCAT-39). Human IKZF1 mRNA was analyzed via TaqMan real-time RT-PCR (Life Technologies).…”