Phospho-tyrosine profiling of mantle cell lymphoma cells suggests the BCR signalling pathway as a potential therapeutic target.

BACKGROUND Very few studies have attempted the investigation of mantle cell lymphoma (MCL) by proteomic tools. We studied MCL cell lines using the PhosphoScan approach. We then investigated the importance of the identified pathways for the survival of MCL cell lines using a functional validation approach. METHODS We analysed MCL cell lines MAVER-1, Jeko-1, Rec-1 and Granta-519. Following phospho-peptide identification, we determined the most represented pathways. For SYK inhibition, we used Piceatannol, determining the LD50 for each cell line. Apoptosis was tested by Annexin V. The modifications of P-SYK and downstream molecules were analysed by flow cytometry, immunofluorescence and western blotting. RESULTS 421 peptides were identified, corresponding to 341 proteins. The most represented pathways suggest the tonic activation of the B-cell receptor signalling. Inhibition of the upstream molecule SYK by Piceatannol, followed by the reduction of downstream target phosphorylation, caused apoptosis of MCL cells. Immunofluorescence studies showed a compartment transition of P-SYK after inhibition. CONCLUSION The BCR signalling pathway is therapeutically promising, and recent data indicate that it might be important in the pathogenesis of B-CLL and DLBCL. Its importance in MCL was suggested by gene expression studies. We show that tonic BCR signalling might be one of the mechanisms driving cell survival and proliferation in MCL, and that the inhibition of SYK might be a viable therapeutic approach. More studies are needed to verify the importance in vivo of this pathway.