Developmental partitioning of SYK and ZAP70 prevents autoimmunity and cancer

Teresa Sadras, Mickaël Martin, Kohei Kume, Mark E. Robinson, Supraja Saravanakumar, Gal Lenz, Zhengshan Chen, Joo Y. Song, Tanya Siddiqi, Laura Oksa, Anne Marie Knapp, Jevon Cutler, Kadriye Nehir Cosgun, Lars Klemm, Veronika Ecker, Janet Winchester, Dana Ghergus, Pauline Soulas-Sprauel, Friedemann Kiefer, Nora HeisterkampAkhilesh Pandey, Vu Ngo, Lili Wang, Hassan Jumaa, Maike Buchner, Jürgen Ruland, Wing Chung Chan, Eric Meffre, Thierry Martin, Markus Müschen

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)2094-2111.e9
JournalMolecular Cell
Issue number10
StatePublished - May 20 2021


  • Anergy
  • B cell selection
  • Kinases
  • Leukemia
  • NFAT
  • Tolerance

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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