Key Points

  • ZAP-70 is essential to maintain a constitutive survival signal for CLL cells and is directly involved in the expression of CCL3 and CCL4.

  • Upon BCR-activation ZAP-70 increasingly forms complexes with ribosomes and promotes MYC-expression and protein synthesis.

The expression of ZAP-70 in a subset of CLL patients strongly correlates with a more aggressive clinical course, though the exact underlying mechanisms remain elusive. The ability of ZAP-70 to enhance B cell receptor (BCR) signaling, independently of its kinase function, is considered to contribute. Here we employed RNA-sequencing and proteomic analyses of primary cells differing only in their expression of ZAP-70 to further define how ZAP-70 increases aggressiveness of CLL. We identified that ZAP-70 is directly required for cell survival in the absence of an overt BCR signal, which can compensate for ZAP-70 deficiency as an anti-apoptotic signal. In addition, the expression of ZAP-70 regulates the transcription of factors regulating recruitment and activation of T cells, such as CCL3, CCL4 and IL4I1. Quantitative mass spectrometry of double-cross linked ZAP-70 complexes further demonstrated constitutive and direct protein-protein interactions between ZAP-70 and BCR-signaling components. Unexpectedly, ZAP-70 also binds to ribosomal proteins, which is not dependent on, but further increased by BCR-stimulation. Importantly, decreased expression of ZAP-70 significantly reduced MYC-expression and global protein synthesis, providing evidence that ZAP-70 contributes to translational dysregulation in CLL. In conclusion, ZAP-70 constitutively promotes cell survival, microenvironment-interactions and protein synthesis in CLL cells, likely to improve cellular fitness and to further drive disease progression.

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