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Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions
Elisa Göckeritz1, Verena Vondey1, Anna Guastafierro1
1Department I of Internal Medicine, University Hospital of Cologne, Centre of Integrated Oncology Cologne-Bonn, CECAD Centre of Excellence on "Cellular Stress Responses in Aging-associated Diseases", University of Cologne, Cologne, Germany.
Abstract:
To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase (BTK) and resistant BTK mutants were employed to dissect target-dependent cellular functions. BTK-C481S and -T474I, expressed in Ramos and NALM-6 cells, maintained BTK auto-phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK-T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor-triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell-intrinsic functions of malignant B cells with importance for their dialogue with the micro-environment.
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