Abstract
SLP65 represents a critical component in (pre-) B cell receptor signal transduction but is compromised in a subset of pre-B cell-derived acute lymphoblastic leukemia. Based on these findings, we investigated (i.) whether SLP65-deficiency also occurs in mature B cell-derived lymphoma and (ii.) whether SLP65-deficient B cell lymphoma cells use an alternative B cell receptor signaling pathway in the absence of SLP65. Indeed, expression of SLP65 protein was also missing in a fraction of B cell lymphoma cases. While SLP65 is essential for B cell receptor-induced Ca2+ mobilization in normal B cells, B cell receptor engagement in SLP65-deficient as compared to SLP65-reconstituted B cell lymphoma cells resulted in an accelerated yet shortlived Ca2+-signal. B cell receptor engagement of SLP65-deficient lymphoma cells involves SRC kinase activation, which is critical for B cell receptor-dependent Ca2+-mobilisation in the absence but not in the presence of SLP65. As shown by RNA interference, the SRC kinase LYN is required for B cell receptor-induced Ca2+ release in SLP65-deficient B cell lymphoma cells but dispensable after SLP65-reconstitution. B cell receptor engagement in SLP65-deficient B cell lymphoma cells also resulted in tyrosine-phosphorylation of the proliferation- and survival-related MAPK1 and STAT5 molecules, which was sensitive to silencing of the SRC kinase LYN. Inhibition of SRC kinase activity resulted in growth arrest and cell death specifically in SLP65-deficient lymphoma cells. These findings indicate that LYN can short-circuit conventional B cell receptor signaling in SLP65-deficient B cell lymphoma cells and thereby promote activation of survival and proliferation-related molecules.
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Accession codes
Abbreviations
- B-CLL:
-
B cell chronic lymphocytic leukemia
- DLBCL:
-
diffuse large B cell lymphoma
- IGH :
-
immunoglobulin heavy-chain
- PBBCL:
-
plasmablastic B cell lymphoma
- SH2:
-
SRC homology domain 2
- siRNA:
-
short interfering RNA
- SLP65:
-
SH2 domain-containing leukocyte protein of 65 kD
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Acknowledgements
We would like to thank Stefanie Jauch for excellent administrative assistance, Paul Hadweh for RT-PCR analysis of SLP65, Professor Dr Maria Wartenberg for Ca2+-measurements and Christoph Goettlinger for cell sorting. NF is supported by a fellowship from the German José-Carreras-Leukemia Foundation. This work was funded by the Deutsche Forschungsgemeinschaft through grants MU1616/2-1, MU1616/3-1 (to MM), the German José-Carreras-Leukemia-Foundation (grant to MM), the Ministry of Science and Research for North Rhine-Westphalia through the Stem Cell Network NRW (to MM), the Deutsche Krebshilfe (through grant ‘Molecular Mechanisms of Malignant Lymphoma’ to RS and MM).
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Sprangers, M., Feldhahn, N., Herzog, S. et al. The SRC family kinase LYN redirects B cell receptor signaling in human SLP65-deficient B cell lymphoma cells. Oncogene 25, 5056–5062 (2006). https://doi.org/10.1038/sj.onc.1209510
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DOI: https://doi.org/10.1038/sj.onc.1209510
