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The tyrosine kinase Syk regulates the survival of chronic lymphocytic leukemia B cells through PKCδ and proteasome-dependent regulation of Mcl-1 expression

Oncogene volume 28, pages 3261–3273 (2009)Cite this article

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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Authors and Affiliations

  1. INSERM UMR576, Nice, France

    A D Baudot, X Mouska, M Ticchioni & M Deckert

  2. University of Nice Sophia-Antipolis, Nice, France

    A D Baudot, P Y Jeandel, S Tartare-Deckert & M Deckert

  3. Department of Internal Medicine, CHU Nice, Nice, France

    P Y Jeandel

  4. Institute for Molecular Medicine and Cell Research, University of Freiburg, Germany

    U Maurer

  5. INSERM UMR895, Nice, France

    S Tartare-Deckert

  6. Genetics Laboratory, CHU Nice, Nice, France

    S D Raynaud

  7. Department of Clinical Hematology, CHU Nice, Nice, France

    J P Cassuto

  8. Immunology Laboratory, CHU Nice, Nice, France

    M Ticchioni

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Correspondence to M Deckert.

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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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