par Stamatopoulos, Basile 
;Meuleman, Nathalie ;De Bruyn, Cécile ;Delforge, Alain ;Bron, Dominique ;Lagneaux, Laurence
Référence Haematologica, 95, 7, page (1136-1143)
Publication Publié, 2010-02
;Meuleman, Nathalie ;De Bruyn, Cécile ;Delforge, Alain ;Bron, Dominique ;Lagneaux, Laurence Référence Haematologica, 95, 7, page (1136-1143)
Publication Publié, 2010-02
Article révisé par les pairs
| Résumé : | Background Chronic lymphocytic leukemia (CLL) is a neoplastic disorder that arises largely as a result of defective apoptosis leading to chemoresistance. Furthermore, SDF-1 and its receptor CXCR4 have been shown to play an important role in CLL cell trafficking and survival. DESIGN AND METHODS: Since histone acetylation is involved in the modulation of gene expression, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells and in particular on cell survival, CXCR4 expression, migration, and drug sensitization. RESULTS: Here, we showed that a 48-hour treatment of SAHA (20 muM) induced a decrease in CLL cell viability via apoptosis (n=20, p=0.0032). Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA significantly decreased CXCR4 mRNA (n=10, p=0.0010) and protein expression (n=40, p<0.0001). As a result, CLL cell migration in response to SDF-1 (n=23, p<0.0001) or through bone marrow stromal cells was dramatically impaired. Consequently, SAHA reduced the protective effect of microenvironment and thus sensitized CLL cells to chemotherapy such as fludarabine. Conclusions In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA in combination with other drugs represents a promising therapeutic approach to inhibiting migration, CLL cell survival and potentially overcoming drug resistance. |
