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

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

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Bruton′s tyrosine kinase (Btk) is a crucial signaling molecule in 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 WT 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.
Original languageEnglish
Pages (from-to)2251-2265
Number of pages15
JournalEuropean Journal of Immunology
Issue number9
Early online date29 Jul 2021
Publication statusPublished - Sep 2021


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