Center of Molecular and Cellular Oncology, Yale Cancer Center, Yale School of Medicine, New Haven, CT, USA; Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
CNRS UPR 3572 "Immunopathology and Therapeutic Chemistry," Institute of Molecular and Cellular Biology (IBMC), Strasbourg, France; Department of Clinical Immunology, Strasbourg University Hospital, Strasbourg, France.
Mol Cell. 2021 May 20;81(10):2094-2111.e9. doi: 10.1016/j.molcel.2021.03.043. Epub 2021 Apr 19.
Even though SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Here, we identified aberrant ZAP70 expression as a common feature in a broad range of B cell malignancies. We validated SYK as the kinase that sets the thresholds for negative selection of autoreactive and premalignant clones. When aberrantly expressed in B cells, ZAP70 competes with SYK at the BCR signalosome and redirects SYK from negative selection to tonic PI3K signaling, thereby promoting B cell survival. In genetic mouse models for B-ALL and B-CLL, conditional expression of Zap70 accelerated disease onset, while genetic deletion impaired malignant transformation. Inducible activation of Zap70 during B cell development compromised negative selection of autoreactive B cells, resulting in pervasive autoantibody production. Strict segregation of the two kinases is critical for normal B cell selection and represents a central safeguard against the development of autoimmune disease and B cell malignancies.
尽管 SYK 和 ZAP70 激酶具有高度的序列同源性，并发挥类似的功能，但它们在 B 和 T 细胞中的表达在整个进化过程中是严格分隔的。在这里，我们发现异常的 ZAP70 表达是广泛的 B 细胞恶性肿瘤的共同特征。我们验证了 SYK 是一种激酶，它为自身反应性和前恶性克隆的阴性选择设定了阈值。当异常表达于 B 细胞时，ZAP70 在 BCR 信号体中与 SYK 竞争，并将 SYK 从阴性选择重定向到持续的 PI3K 信号，从而促进 B 细胞存活。在 B-ALL 和 B-CLL 的遗传小鼠模型中，Zap70 的条件表达加速了疾病的发生，而基因缺失则损害了恶性转化。在 B 细胞发育过程中诱导性激活 Zap70 会损害自身反应性 B 细胞的阴性选择，导致广泛的自身抗体产生。两种激酶的严格分离对于正常 B 细胞的选择至关重要，是防止自身免疫性疾病和 B 细胞恶性肿瘤发展的中心保障。
