Chronic lymphocytic leukemia (CLL) is characterized by constitutive activation 
of the B-cell receptor (BCR) signaling pathway, but variable responsiveness of 
the BCR to antigen ligation. Bruton's tyrosine kinase (BTK) shows constitutive 
activity in CLL and is the target of irreversible inhibition by ibrutinib, an 
orally bioavailable kinase inhibitor that has shown outstanding activity in CLL. 
Early clinical results in CLL with other reversible and irreversible BTK 
inhibitors have been less promising, however, raising the question of whether 
BTK kinase activity is an important target of ibrutinib and also in CLL. To 
determine the role of BTK in CLL, we used patient samples and the Eμ-TCL1 (TCL1) 
transgenic mouse model of CLL, which results in spontaneous leukemia 
development. Inhibition of BTK in primary human CLL cells by small interfering 
RNA promotes apoptosis. Inhibition of BTK kinase activity through either 
targeted genetic inactivation or ibrutinib in the TCL1 mouse significantly 
delays the development of CLL, demonstrating that BTK is a critical kinase for 
CLL development and expansion and thus an important target of ibrutinib. 
Collectively, our data confirm the importance of kinase-functional BTK in CLL.