Published online 10 March 2009
Haematologica, Vol 94, Issue 4, 507-517 doi:10.3324/haematol.13690
Copyright © 2009 by Ferrata Storti Foundation
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Chronic Lymphocytic Leukemia

Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton

Sandrine Barbier1,2,3,4, Laurent Chatre4, Marlène Bras4, Patricia Sancho4, Gaël Roué4, Clémence Virely4, Victor J. Yuste4, Sylvie Baudet5, Manuel Rubio6, Josep E. Esquerda7, Marika Sarfati6, Hélène Merle-Béral1,2,3,5, Santos A. Susin1,2,3,4

1 INSERM, U872, Mort Cellulaire Programmée et Physiopathologie des Cellules Tumorales, Equipe 19, Centre de Recherche des Cordeliers, Paris, France
2 Université Pierre et Marie Curie-Paris 6, UMRS 872, Paris, France
3 Université Paris Descartes, UMRS 872, Paris, France
4 Institut Pasteur, Paris, France
5 AP-HP, Groupe Hospitalier Pitie-Salpêtrière, Service d'Hématologie Biologique, Paris, France
6 Centre de Recherche du CHUM, Hôpital Notre-Dame, Laboratoire d’Immunorégulation, Montréal, Canada
7 Cell Neurobiology Unit, Departament de Medicina Experimental, Universitat de Lleida, IRBLLEIDA, Lleida, Spain

Correspondence: Santos A. Susin. Centre de Recherche des Cordeliers. 15, rue de l’Ecole de Médecine, 75006, Paris, France. E-mail:santos.susin{at}crc.jussieu.fr

Background: Programmed cell death has been traditionally related with caspase activation. However, it is now accepted that caspase-independent forms of programmed cell death also regulate cell death. In chronic lymphocytic leukemia, CD47 ligation induces one of these alternative forms of cell death: type III programmed cell death. This poorly understood process is characterized by cytoplasmic hallmarks, such as mitochondrial damage. To gain insights into the molecular pathways regulating type III programmed cell death in chronic lymphocytic leukemia, we performed extensive biochemical and cell biology assessments.

Design and Methods: After CD47 triggering, purified B-cells from 20 patients with chronic lymphocytic leukemia were studied by flow cytometry, immunofluorescence and three-dimensional imaging, immunoblotting, electron microscopy, and fibrillar/globular actin measurements. Finally, we subjected CD47-treated chronic lymphocytic leukemia cells to a phagocytosis assay.

Results: We first confirmed that induction of type III programmed cell death is an efficient means of triggering cell death in chronic lymphocytic leukemia. Further, we demonstrated that the signaling events induced by CD47 ligation provoked a reduction in cell size. This alteration is related to F-actin disruption, as the two other cytoskeleton networks, microtubules and intermediate filaments, remain undisturbed in type III programmed cell death. Strikingly, we revealed that the pharmacological modulation of F-actin dynamics regulated this type of death. Finally, our data delineated a new programmed cell death pathway in chronic lymphocytic leukemia initiated by CD47 triggering, and followed by serine protease activation, F-actin rearrangement, mitochondrial damage, phosphatidylserine exposure, and cell clearance.

Conclusions: Our work reveals a key molecular tool in the modulation of cell death in chronic lymphocytic leukemia: F-actin. By assessing the regulation of F-actin and type III programmed cell death, this analysis provides new options for destroying chronic lymphocytic leukemia cells, such as a combination of therapies based on apoptosis regulators (e.g., caspases, Bcl-2, Bax) along with alternative therapies based on type III death effectors (e.g., F-actin).

Key words: actin, apoptosis, caspase-independent cell death, CD47, chronic lymphocytic leukemia, mitochondria.