Sadras, T., Martin, M., Kume, K., Robinson, M. E., Saravanakumar, S., Lenz, G., Chen, Z., Song, J. Y., Siddiqi, T., Oksa, L., Knapp, A. M., Cutler, J., Cosgun, K. N., Klemm, L., Ecker, V., Winchester, J., Ghergus, D., Soulas-Sprauel, P., Kiefer, F., Heisterkamp, N., Pandey, A., Ngo, V., Wang, L., Jumaa, H., Buchner, M., Ruland, J., Chan, W. C., Meffre, E., Martin, T., Muschen, M. (2021). Mol Cell 81, 2094-2111 e2099.
DOI:10.1016/j.molcel.2021.03.043(link is external)
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.
