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SYK and ZAP70 kinases in lymphocyte selection

Award Number: R01AI164692
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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SYK and ZAP70 kinases in lymphocyte selection - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $598,819 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	4	3/10/2025	NON-COMPETING CONTINUATION	$598,819
														Subtotal = $598,819

Issue Date FY: 2024 ( Subtotal = $617,340 )
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	3	1/24/2024	NON-COMPETING CONTINUATION	$555,606
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	001	3	5/23/2024	NON-COMPETING CONTINUATION	$61,734
														Subtotal = $617,340

Issue Date FY: 2023 ( Subtotal = $617,340 )
2023	2023	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	2	1/18/2023	NON-COMPETING CONTINUATION	$617,340
														Subtotal = $617,340

Issue Date FY: 2022 ( Subtotal = $617,340 )
2022	2022	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Allergy and Infectious Diseases Research	000	1	1/28/2022	NEW	$617,340
														Subtotal = $617,340

Grand Total All Awards = $2,450,839

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SYK and ZAP70 kinases in lymphocyte selection

Award Number: R01AI164692

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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