| First Author | Rip J | Year | 2021 |
| Journal | Eur J Immunol | Volume | 51 |
| Issue | 9 | Pages | 2251-2265 |
| PubMed ID | 34323286 | Mgi Jnum | J:309482 |
| Mgi Id | MGI:6758616 | Doi | 10.1002/eji.202048968 |
| Citation | Rip J, et al. (2021) Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice. Eur J Immunol 51(9):2251-2265 |
| abstractText | 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-kappaB 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 PLCgamma2 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-PLCgamma2 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. |
