HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Sainz-Perez, A. Articles by Dalloul, A. Search for Related Content PubMed PubMed Citation Articles by Sainz-Perez, A. Articles by Dalloul, A.

IL-24 Induces Apoptosis of Chronic Lymphocytic Leukemia B Cells Engaged into the Cell Cycle through Dephosphorylation of STAT3 and Stabilization of p53 Expression

Alexander Sainz-Perez^1,2,*, Hélène Gary-Gouy^1,*, Françoise Gaudin^*, Ghyath Maarof^*, Anne Marfaing-Koka, Thierry de Revel and Ali Dalloul^3,*

^* Institut National de la Santé et de la Recherche Médicale U764, IFR 13, Université Paris XI, Clamart, France; Laboratoire d’Hématologie, Hôpital Antoine Béclère, Clamart, France; and Service d’Hématologie, Hôpital d’Instruction des Armées Percy, Clamart, France

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of long-lived monoclonal B cells mostly arrested at the G₀/G₁ phase of the cell cycle. CLL cells strongly express intracellular melanoma differentiation-associated gene-7 (MDA7)/IL-24. However, adenovirus-delivered MDA7 was reported to be cytotoxic in several tumor cell lines. We report herein that rIL-24 alone had no effect; however, sequential incubation with rIL-2 and rIL-24 reduced thymidine incorporation by 50% and induced apoptosis of CLL cells in S and G₂/M phases of the cell cycle, but not of normal adult blood or tonsil B cells. IL-24 stimulated STAT3 phosphorylation in IL-24R1-transfected cells but not in normal or CLL B cells. In contrast, IL-24 reversed the IL-2-induced phosphorylation of STAT3 in CLL, and this effect was neutralized by anti-IL-24 Ab. Phospho- (P)STAT3 inhibition induced by IL-24 was reversed by pervanadate, an inhibitor of tyrosine phosphatases. The addition of rIL-24 to IL-2-activated CLL B cells resulted in increases of transcription, protein synthesis. and phosphorylation of p53. The biological effects of IL-24 were reversed by the p53 inhibitor pifithrin- and partly by the caspase inhibitor zvad. Troglitazone (a protein tyrosine phosphatase, PTP1B activator) phosphatase inhibited PSTAT3 and augmented p53 expression. PSTAT3 is a transcriptional repressor of p53, and therefore IL-24 induction of p53 secondary to PSTAT3 dephosphorylation may be sensed as a stress signal and promote apoptosis in cycling cells. This model explains why IL-24 can protect some resting/differentiated cells and be deleterious to proliferating cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ A.S.-P. and H.G.-G. contributed equally to this work.

² Current address: Département d’Immunologie, Bâtiment Metchnikoff, 2ème Étage, Institut Pasteur, 25 Rue du Dr. Roux, Paris 75524, France.

³ Address correspondence and reprint requests to Dr. A. H. Dalloul, Unité de Thérapie Cellulaire (UTCT), Hôpital Universitaire de Nancy-Brabois, Nancy 54000 France. E-mail address: a.dalloul{at}chu-nancy.fr

⁴ Abbreviations used in this paper: MDA7, melanoma differentiation-associated gene-7; CLL, chronic lymphocytic leukemia; pft-, pifithrin-; PI, propidium iodide; PSTAT3, phospho STAT3; PTP1B, protein tyrosine phosphatase 1B; TG, troglitazone; FSC, forward scatter.