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

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2009Author
Barbier, Sardine
Chatre, Laurent
Bras, Marlène
Sancho, Patricia
Roué, Gaël
Virely, Clémence
Yuste Mateos, Víctor J. (Víctor José)
Baudet, Sylvie
Rubio, Manuel
Sarfati, Marika
Merle-Béral, Hélène
Susin, Santos A.
Suggested citation
Barbier, Sardine;
Chatre, Laurent;
Bras, Marlène;
Sancho, Patricia;
Roué, Gaël;
Virely, Clémence;
...
Susin, Santos A..
(2009)
.
Caspase-independent type III programmed cell death in chronic lymphocytic leukemia: the key role of the F-actin cytoskeleton.
Haematologica, 2009, vol. 94, núm. 4, p. 507-517.
https://doi.org/10.3324/haematol.13690.
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Show full item recordAbstract
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).
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Haematologica, 2009, vol. 94, núm. 4, p. 507-517European research projects
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