IMiD immunomodulatory compounds block C/EBP{beta} translation through eIF4E down-regulation resulting in inhibition of MM.
Blood
; 117(19): 5157-65, 2011 May 12.
Article
em En
| MEDLINE
| ID: mdl-21389327
ABSTRACT
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-ß (C/EBPß) resulting in abrogation of cell proliferation. Overexpression of C/EBPß rescued MM cells from IMiD-induced inhibition of proliferation, indicating that C/EBPß is critical in mediating antiproliferative effects. IMiD-induced decrease of C/EBPß 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 CD138âº/IRF4⺠double labeling. In contrast to down-regulation of C/EBPß protein, IMiD compounds did not alter C/EBPß mRNA levels or protein stability, suggesting translational regulation of C/EBPß. We could demonstrate that C/EBPß protein expression is under eIF4E-translational control in MM. Furthermore, inhibition of the eIF4E-C/EBPß 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.
Texto completo:
1
Coleções:
01-internacional
Contexto em Saúde:
6_ODS3_enfermedades_notrasmisibles
Base de dados:
MEDLINE
Assunto principal:
Regulação da Expressão Gênica
/
Proteína beta Intensificadora de Ligação a CCAAT
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Fator de Iniciação 4E em Eucariotos
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Fatores Imunológicos
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Mieloma Múltiplo
Tipo de estudo:
Observational_studies
Limite:
Humans
Idioma:
En
Revista:
Blood
Ano de publicação:
2011
Tipo de documento:
Article