1. ¹Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany
2. ²Max-Planck-Institute for Immunobiology, Freiburg, Germany
3. ³Department of Pathology, Universiät Frankfurt, Frankfurt, Germany
4. ⁴Institute for Neurophysiology, Universität zu Köln, Köln, Germany
5. ⁵Institute of Human Genetics, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany

Correspondence: M Müschen, Laboratory for Molecular Stem Cell Biology, Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, Düsseldorf 40225, Germany. E-mail: markus.mueschen@uni-duesseldorf.de

Received 12 September 2005; Revised 16 January 2006; Accepted 16 January 2006; Published online 27 March 2006.

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.