Abstract
B-cell chronic lymphocytic leukemia (B-CLL) is characterized by accumulation of mature monoclonal CD5+ B cells. The disease results mainly from a failure of cells to undergo apoptosis, a process largely influenced by the existence of constitutively activated components of B-cell receptor signaling and the deregulated expression of anti-apoptotic molecules. Recent evidence pointing to a critical role of spleen tyrosine kinase (Syk) in ligand-independent BCR signaling prompted us to examine its role in primary B-CLL cell survival. We demonstrate that pharmacological inhibition of constitutive Syk activity and silencing by siRNA led to a dramatic decrease of cell viability in CLL samples (n=44), regardless of clinical and biological status and induced typical apoptotic cell death with mitochondrial failure followed by caspase 3-dependent cell death. We also provide functional and biochemical evidence that Syk regulated B-CLL cell survival through a novel pathway involving PKCδ and a proteasome-dependent regulation of the anti-apoptotic protein Mcl-1. Together, our observations are consistent with a model wherein PKCδ downstream of Syk stabilizes Mcl-1 through inhibitory phosphorylation of GSK3 by Akt. We conclude that Syk constitutes a key regulator of B-CLL cell survival, emphasizing the clinical utility of Syk inhibition in hematopoietic malignancies.
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Abbreviations
- B-CLL:
-
B-chronic lymphocytic leukemia
- BCR:
-
B-cell receptor
- ERK:
-
extracellular signal-regulated kinase
- GSK-3:
-
Glycogen synthase kinase-3
- MAPK:
-
mitogen-activated protein kinase
- Mcl-1:
-
myeloid cell leukemia sequence 1
- PI3K:
-
phosphatidyl 3-kinase
- PKC:
-
protein kinase C
- PLCγ2:
-
phospholipase Cγ2
- siRNA:
-
small-interfering RNA
- XIAP:
-
X-linked inhibitor of apoptosis protein
- ZAP-70:
-
zeta-associated protein at 70 kDa
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Acknowledgements
This work was supported by INSERM, ARC (Grant No 3111), and INCa (Grant PL-06-026). ADB is a recipient of an INSERM-Région Provence Alpes Côte d’Azur PhD fellowship in partnership with TxCell (Valbonne, France). M Deckert is a recipient of a Contrat d’Interface Clinique with the Department of Clinical Hematology, CHU de Nice. We thank P Gounon (CCMA, Faculté des Sciences, Nice) for electron microscopy analysis, and M. Ciosi (INRA-CNRS, Sophia-Antipolis) for statistical analysis.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)
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Baudot, A., Jeandel, P., Mouska, X. et al. The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression. Oncogene 28, 3261–3273 (2009). https://doi.org/10.1038/onc.2009.179
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DOI: https://doi.org/10.1038/onc.2009.179
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