Search

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. [Display omitted] • ZAP70 is aberrantly coexpressed with SYK in a broad range of B cell malignancies • Forced Zap70 expression in vivo disrupts negative selection of autoreactive B cells • ZAP70 diverts SYK from NFAT-dependent anergy to PI3K-dependent survival signaling • Zap70 prevents NFAT-dependent anergy and accelerates B cell transformation Although SYK and ZAP70 are segregated in normal B and T lymphocytes, Sadras et al. show that aberrant ZAP70 coexpression is common across multiple B cell malignancies. By competing with SYK, ZAP70 diverts BCR signaling from NFAT to PI3K activation, which disables mechanisms of negative selection of autoreactive or premalignant B cell clones. [ABSTRACT FROM AUTHOR]