Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice.

Rip, Jasper; de Bruijn, Marjolein J W; Neys, Stefan F H; Singh, Simar Pal; Willar, Jonas; van Hulst, Jennifer A C; Hendriks, Rudi W; Corneth, Odilia B J

Bruton's tyrosine kinase (Btk) is a crucial signaling molecule in B-cell receptor (BCR) signaling and a key regulator of B cell differentiation and function. Btk inhibition has shown impressive clinical efficacy in various B cell malignancies. However, it remains unknown whether inhibition additionally induces changes in BCR signaling due to feedback mechanisms, a phenomenon referred to as BCR rewiring. In this report, we studied the impact of Btk activity on major components of the BCR signaling pathway in mice. As expected, NF-κB and Akt/S6 signaling was decreased in Btk-deficient B cells. Unexpectedly, phosphorylation of several proximal signaling molecules including CD79a, Syk and PI3K, as well as the key Btk-effector PLCγ2 and the more downstream kinase Erk were significantly increased. This pattern of BCR rewiring was essentially opposite in B cells from transgenic mice overexpressing Btk. Importantly, prolonged Btk inhibitor treatment of wild-type mice or mice engrafted with leukemic B cells also resulted in increased phosho-CD79a and phospho-PLCγ2 in B cells. Our findings show that Btk enzymatic function determines phosphorylation of proximal and distal BCR signaling molecules in B cells. We conclude that Btk inhibitor treatment results in rewiring of BCR signaling, which may affect both malignant and healthy B cells. This article is protected by copyright. All rights reserved.