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SYK and ZAP70 kinases in lymphocyte selection

SYK 和 ZAP70 激酶在淋巴细胞选择中的作用

基本信息

批准号：
10557882
负责人：
Eric Meffre
金额：
$ 61.73万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557882
关键词：
Ablation Acceleration Acute Alleles Antibodies Autoantibodies Autoimmune Diseases B lymphoid malignancy B-Cell Acute Lymphoblastic Leukemia B-Cell Antigen Receptor B-Cell Development B-Cell Lymphomas B-Cell Neoplasm B-Lymphocytes BLNK gene Biological Markers Calcium Signaling Cell Death Cell Proliferation Cell Survival Cells Chronic Lymphocytic Leukemia Clonal Deletion Clone Cells Development Dominant-Negative Mutation Engineering Etiology Evolution Flare Frequencies Genetic Genetic study Human Impairment Knock-in Lymphocyte Malignant - descriptor Mediating Mus Oncogenes Oncogenic Onset of illness Output PIK3CG gene Pathologic Patients Peripheral Phosphoric Monoester Hydrolases Phosphotransferases Preclinical Testing Production Protein Analysis Receptor Signaling Reporting Reverse Transcriptase Polymerase Chain Reaction Rheumatoid Arthritis SYK gene Signal Transduction Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Cell Development T-Cell Lymphoma T-Cell Receptor T-Lymphocyte Testing ZAP-70 Gene analog anergy autoreactive B cell autoreactivity cell transformation humanized mouse inducible gene expression loss of function mouse model mutant novel optogenetics patient derived xenograft model pharmacologic phosphoproteomics premalignant pressure prevent promoter remote control segregation single cell proteins small molecule inhibitor stoichiometry

项目摘要

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.

摘要