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

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Bruton's tyrosine kinase inhibition induces rewiring of proximal and distal B-cell receptor signaling in mice
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-07-29 , DOI: 10.1002/eji.202048968
Jasper Rip ₁ , Marjolein J W de Bruijn ₁ , Stefan F H Neys ₁ , Simar Pal Singh ₁ , Jonas Willar ₂ , Jennifer A C van Hulst ₁ , Rudi W Hendriks ₁ , Odilia B J Corneth ₁

Affiliation

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.

中文翻译：

布鲁顿的酪氨酸激酶抑制诱导小鼠近端和远端 B 细胞受体信号的重新布线

布鲁顿酪氨酸激酶 (Btk) 是 BCR 信号传导中的关键信号分子，也是 B 细胞分化和功能的关键调节因子。Btk 抑制在各种 B 细胞恶性肿瘤中显示出令人印象深刻的临床疗效。然而，由于反馈机制，抑制是否会额外引起 BCR 信号的变化，这种现象被称为 BCR 重新布线，这仍然是未知的。在本报告中，我们研究了 Btk 活性对小鼠 BCR 信号通路主要成分的影响。正如所料，NF-κB 和 Akt/S6 信号在 Btk 缺陷 B 细胞中减少。出乎意料的是，几个近端信号分子的磷酸化，包括 CD79a、Syk 和 PI3K，以及关键的 Btk 效应子 PLCγ2 和更下游的激酶 Erk，显着增加。这种 BCR 重新布线模式在来自过表达 Btk 的转基因小鼠的 B 细胞中基本相反。重要的是，延长 Btk 抑制剂治疗 WT 小鼠或移植有白血病 B 细胞的小鼠也导致 B 细胞中 phosho-CD79a 和 phospho-PLCγ2 增加。我们的研究结果表明，Btk 酶促功能决定了 B 细胞中近端和远端 BCR 信号分子的磷酸化。我们得出结论，Btk 抑制剂治疗导致 BCR 信号的重新布线，这可能影响恶性和健康 B 细胞。我们的研究结果表明，Btk 酶促功能决定了 B 细胞中近端和远端 BCR 信号分子的磷酸化。我们得出结论，Btk 抑制剂治疗导致 BCR 信号的重新布线，这可能影响恶性和健康 B 细胞。我们的研究结果表明，Btk 酶促功能决定了 B 细胞中近端和远端 BCR 信号分子的磷酸化。我们得出结论，Btk 抑制剂治疗导致 BCR 信号的重新布线，这可能影响恶性和健康 B 细胞。

更新日期：2021-09-01

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