Journal
BLOOD
Volume 137, Issue 26, Pages 3629-3640Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2020009960
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Funding
- Kay Kendell Foundation [KKL1070]
- Cancer Research UK (CRUK) [C49940/A17480]
- Specialist Programme from Blood Cancer UK [12048]
- UK Medical Research Council [MR/T012412/1]
- Kay Kendall Leukaemia Fund
- Wellcome strategic award [100140]
- Wellcome
- Connor Wright Project
- Cambridge National Institute for Health Research Biomedical Research Centre
- European Cooperation in Science and Technology Action European Network for Innovative Diagnosis and treatment of Chronic Neutropenias [CA18233]
- MRC [MR/T012412/1, MC_U105161083, MR/L003368/1] Funding Source: UKRI
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The expression of ZAP-70 in CLL patients is associated with aggressive clinical course. ZAP-70 enhances BCR signaling and cell survival, regulates T cell recruitment and activation, and interacts with BCR-signaling components. ZAP-70 also binds to ribosomal proteins and contributes to translational dysregulation in CLL.
The expression of ZAP-70 in a subset of chronic lymphocytic leukemia (CLL) patients strongly correlates with a more aggressive clinical course, although 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. We used RNA-sequencing and proteomic analyses of primary cells differing only in their expression of ZAP-70 to further define how ZAP-70 increases the 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 antiapoptotic signal. In addition, the expression of ZAP-70 regulates the transcription of factors regulating the 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 is 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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