Journal article

Publication year: 2021

Pages: 3629-3640

Journal: Blood

Volume number: 137

Issue number: 26

ISSN: 0006-4971

Open access status: Green

DOI Link: https://doi.org/10.1182/blood.2020009960

Publisher: American Society of Hematology (ASH Publications)

Abstract: 
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.

Harvard Citation style: Chen, J., Sathiaseelan, V., Moore, A., Tan, S., Chilamakuri, C., Franklin, V., et al. (2021) ZAP-70 constitutively regulates gene expression and protein synthesis in chronic lymphocytic leukemia, Blood, 137(26), pp. 3629-3640. https://doi.org/10.1182/blood.2020009960

APA Citation style: Chen, J., Sathiaseelan, V., Moore, A., Tan, S., Chilamakuri, C., Franklin, V., Shahsavari, A., Jakwerth, C., Hake, S., Warren, A., Mohorianu, I., D'Santos, C., & Ringshausen, I. (2021). ZAP-70 constitutively regulates gene expression and protein synthesis in chronic lymphocytic leukemia. Blood. 137(26), 3629-3640. https://doi.org/10.1182/blood.2020009960