Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice
Rip J, De Bruijn MJW, Neys SFH, Singh SP, Willar J, Van Hulst JAC, Hendriks RW, Corneth OBJ (2021)
Publication Type: Journal article
Publication year: 2021
Journal
Abstract
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-kappa B 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 PLC gamma 2 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-PLC gamma 2 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.
Involved external institutions
Netherlands (NL)How to cite
APA:
Rip, J., De Bruijn, M.J.W., Neys, S.F.H., Singh, S.P., Willar, J., Van Hulst, J.A.C.,... Corneth, O.B.J. (2021). Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice. European Journal of Immunology. https://dx.doi.org/10.1002/eji.202048968
MLA:
Rip, Jasper, et al. "Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice." European Journal of Immunology (2021).
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