Journal
MOLECULAR CELL
Volume 81, Issue 10, Pages 2094-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2021.03.043
Keywords
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Funding
- UPR CNRS [3572]
- NIH through a National Cancer Institute (NCI) Outstanding Investigator Award [R35CA197628, R01CA157644, R01CA213138, P01CA233412]
- Howard Hughes Medical Institute [HHMI-55108547]
- Arthur H. and Isabel Bunker Chair in Hematology
- Blood Cancer Discoveries Grant Program through the Leukemia & Lymphoma Society
- Mark Foundation For Cancer Research
- Paul G. Allen Frontiers Group
- V Foundation for Cancer Research [T2018-003B]
- NIH/National Institute of Allergy and Infectious Diseases (NIAID) [AI061093, AI118855]
- Lupus Research Alliance
- foundation Alsace contre le Cancer
- foundation Groupe Pasteur Mutualite
- foundation CSL Behring
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Although SYK and ZAP70 kinases share high sequence homology and serve analogous functions, their expression in B and T cells is strictly segregated throughout evolution. Aberrant ZAP70 expression is identified as a common feature in various B cell malignancies. The strict segregation of the two kinases is crucial for normal B cell selection and acts as a central safeguard against autoimmune diseases and B cell malignancies.
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.
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