BMSEHA15
Published online 9 February 2010
(Haematologica 2010, 10.3324/haematol.2009.013847)
Copyright © 2010 by Ferrata Storti Foundation
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Article

The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA) induces apoptosis, downregulates the CXCR4 chemokine receptor and impairs migration of chronic lymphocytic leukemia cells

Basile Stamatopoulos, Nathalie Meuleman, Cécile De Bruyn, Alain Delforge, Dominique Bron, Laurence Lagneaux

Laboratory of Experimental Hematology, Faculty of Medicine, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Brussels, Belgium

Correspondence: Basile Stamatopoulos, Université Libre de Bruxelles, Institut Jules Bordet, Laboratoire d'Hématologie Expérimentale, Boulevard de Waterloo n° 121, 1000 Bruxelles, Belgium. Phone: international +32(0)2.5413722. Fax: international +32 (0)2.5413453. E-mail: bstamato{at}ulb.ac.be

ABSTRACT

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 µM) 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.

Key words: SAHA, chronic lymphocytic leukemia, CXCR4, migration.