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Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE148797 | GEO | 2021/05/21

REPOSITORIES: GEO

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Lck promotes Zap70-dependent LAT phosphorylation by bridging Zap70 to LAT

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Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

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