Establishing a chemical genetic link between Bruton tyrosine kinase activity in malignant B cells and cell functions involved in the micro‐environmental dialogue

Summary 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.