Effect of the Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid (SAHA) On Chronic Lymphocytic Leukemia Cells: Apoptosis, Migration Impairment and Drug Sensitization.

Abstract 3435

Poster Board III-323

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 has been shown to play an important role in CLL cell trafficking and survival. Since histone acetylation is involved in the modulation of gene expression, cellular differentiation, and survival, we evaluated the effects of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on CLL cells in vitro and in particular on cell survival, CXCR4 expression, migration and in combination with different chemotherapies. Here, we showed that a 48-hour treatment of SAHA induced a dose-dependent decrease in CLL cell viability via apoptosis (n=20, p=0.0032). This effect was also seen in previously untreated and chemoresistant CLL patients. Using specific caspase inhibitors, we demonstrated the participation of caspases-3, -6 and -8, suggesting an activation of the extrinsic pathway. Additionally, SAHA decreased actin polymerization (about 45%) in response to SDF-1 (n=6, p=0.0313). SAHA also significantly decreased CXCR4 mRNA (n=10, p=0.0010) and protein expression (n=25, p<0.0001). Consequently, CLL cell migration in response to SDF-1 (n=17, p=0.0003) or through bone marrow stromal cells (pseudoemperipolesis) was dramatically impaired. Finally, SAHA at low concentration (5μM) could increase sensitivity of CLL cells to fludarabine, flavopiridol, thalidomide or bortezomib. In conclusion, SAHA induces apoptosis in CLL cells via the extrinsic pathway and downregulates CXCR4 expression leading to decreased cell migration. SAHA (alone or in combination with other drugs) represents thus a promising therapeutic approach to inhibiting migration, inducing apoptosis in CLL cell and potentially overcoming drug resistance.