| First Author | Sadras T | Year | 2021 |
| Journal | Mol Cell | Volume | 81 |
| Issue | 10 | Pages | 2094-2111.e9 |
| PubMed ID | 33878293 | Mgi Jnum | J:307147 |
| Mgi Id | MGI:6718906 | Doi | 10.1016/j.molcel.2021.03.043 |
| Citation | Sadras T, et al. (2021) Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer. Mol Cell 81(10):2094-2111.e9 |
| abstractText | 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. |
