The role of SYK and ZAP70 kinases in the etiology of B-cell malignancies
Final Report Abstract
The survival and proliferation of B and T lymphocytes are governed by a precisely regulated BCR/TCR signaling network. Central to immune receptor signaling are the kinases SYK in B cells and ZAP70 in T cells—highly homologous proteins with distinct expression patterns in normal B and T cells. However, we have previously shown frequent co-expression of ZAP70 not only in chronic lymphocytic leukemia (CLL), where this has been extensively studied, but also in B-acute lymphoblastic leukemia (B-ALL) and mantle cell lymphoma (MCL). We demonstrated that ZAP70 expression is characteristic of B cell malignancies arising from B cells that have not yet encountered germinal centers. We characterized ZAP70 as a dominant-negative counterpart to SYK, which buffers excessive BCR signaling, redirecting it towards PI3K-CD19, limiting calcium release, and avoiding negative selection of B cells via NFAT activation. However, the role of ZAP70 in the oncogenic transformation of B cell precursors has remained unclear, and the transcriptional mechanisms behind atypical ZAP70 expression in B cells are yet to be fully understood. In this study, we employ multiple ex vivo approaches and an in vivo model of leukemic B cell transformation to show that ZAP70 expression accelerates leukemogenesis by precisely balancing the activity of various oncogenic drivers. We also identified downregulation of NFATC2 as a mechanism for bypassing increased oncogenic stress in the absence of ZAP70 during transformation. Interestingly, and consistent with clinical data, we utilized an endogenous chemogenetic degradation model of ZAP70 in early B cell malignancies, demonstrating that their survival and proliferation do not rely on ZAP70 expression, even though its role as a negative regulator of BCR signaling remains intact. Through genomic locus proteomics, we identified MYB and ETS1, well-known transcriptional regulators essential to the B cell lineage, as key factors in tightly controlling ZAP70 expression. Finally, we found that βcatenin binds to RUNX1 to activate ZAP70 transcription in malignant early B cells and can induce de novo ZAP70 expression independently of the B cell origin.
Publications
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Separation of B- and T-Cell-Specific Signaling Molecules Prevents Oncogenic Transformation in Lymphoid Malignancies. Blood, 142(Supplement 1), 1396-1396.
Ketzer, Franz; Klemm, Lars; Robinson, Mark E.; Loucks, Christian; Arce, David Fonseca; Cosgun, Kadriye Nehir; Kothari, Shalin & Müschen, Markus
