# SYK and ZAP70 kinases in lymphocyte selection

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $617,340

## Abstract

ABSTRACT
While B-cells are under intense selective pressure to eliminate autoreactive and pre-malignant clones,
we identified SYK as central kinase to set the thresholds for negative selection. SYK and its highly
homologous relative ZAP70 initiate B-cell receptor (BCR) and T-cell receptor (TCR) signaling in B- and
T-lymphocytes, respectively. Even though the two kinases are almost identical and serve analogous
functions, their expression in B- and T-cells is strictly segregated throughout evolution. Whereas the
reason for separation of the two kinases is not known, aberrant coexpression of Syk and Zap70 was
previously reported in B-cell chronic lymphocytic leukemia (CLL) and in peripheral T-cell lymphoma
(PTCL). Our group recently demonstrated that aberrant ZAP70 expression is a common feature in pre-
germinal center (GC) B-cell malignancies (B-ALL, CLL, MCL; Sadras et al., Mol Cell 2021). In genetic
mouse models for B-ALL and B-CLL, inducible coexpression of Zap70 accelerated disease onset, while
genetic deletion impaired malignant transformation. Likewise, inducible expression of Zap70 during
early B-cell development subverted negative selection of autoreactive B-cells to promote pervasive
autoantibody production.
Mechanistically, ZAP70 competes with SYK and exerts a dominant-negative effect on SYK-dependent
Ca2+-signaling. By occupying but not phosphorylating BLNK, BTK and PLC2 substrates upstream of
calcium signaling, ZAP70 dramatically reduces the frequency of autonomous Ca2+-oscillations. Fast
oscillations in the sole presence of SYK (4.5 mHz) are decoded by NFATC1 and result in anergy and
cell death. In contrast, slow Ca2+-oscillations in the presence of ZAP70 (0.25 mHz) promote selective
activation of NF-B and B-cell survival and proliferation.
We test here the central hypothesis that B-cells sense pathological signaling downstream of an
autoreactive BCR or a transforming oncogene through SYK-dependent high-frequency Ca2+-
oscillations. At high frequencies, Ca2+-oscillations activate NFATC1 to initiate B-cell anergy and clonal
deletion. Conversely, ZAP70 slows down Ca2+-oscillations to activate NF-B instead of NFATC1 and
enables autoreactive and premalignant B-cell clones to persist and eventually give rise to autoimmune
disease or pre-GC B-cell malignancies.
We are proposing three Aims to (1) elucidate the mechanisms by which ZAP70 slows down SYK-
dependent high-frequency Ca2+-oscillations, to (2) determine how coexpression of ZAP70 subverts
negative selection of autoreactive B-cells in autoimmune disease and (3) to uncover how ZAP70
enables oncogenic signaling and overt malignant transformation of pre-malignant B-cells.

## Key facts

- **NIH application ID:** 10765633
- **Project number:** 5R01AI164692-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Eric Meffre
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $617,340
- **Award type:** 5
- **Project period:** 2022-02-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10765633

## Citation

> US National Institutes of Health, RePORTER application 10765633, SYK and ZAP70 kinases in lymphocyte selection (5R01AI164692-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10765633. Licensed CC0.

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