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Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma

Abstract

Primary effusion lymphoma (PEL) is a highly aggressive B-cell malignancy that is closely associated with one of oncogenic viruses infection, Kaposi’s sarcoma-associated herpesvirus. PEL prognosis is poor and patients barely survive >6 months even following active chemotherapy interventions. There is therefore an urgent need to discover more effective targets for PEL management. We recently found that the ribonucleotide reductase (RR) subunit M2 is potentially regulated by the key oncogenic hepatocyte growth factor/c-MET pathway in PEL. In this study, we set to investigate the role of RR in PEL pathogenesis and to evaluate its potential as a therapeutic target. We report that the RR inhibitor 3-AP actively induces PEL cell cycle arrest through inhibiting the activity of the nuclear factor-κB pathway. Using a xenograft model, we found that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) effectively suppresses PEL progression in immunodeficient mice. Transcriptome analysis of 3-AP-treated PEL cell lines reveals altered cellular genes, most of whose roles in PEL have not yet been reported. Taken together, we propose that RR and its signaling pathway may serve as novel actionable targets for PEL management.

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Acknowledgements

This work was partially supported by grants from a DOD Career Development Award (CA140437), the Leukemia Research Foundation, the Louisiana Clinical and Translational Science Center Pilot grants (U54GM104940 from NIH), NIH RO1s (AI101046 and AI106676), as well as awards from the National Natural Science Foundation of China (81472547, 81672924 and 81400164). Funding sources had no role in the study design, data collection/analysis, decision to publish and/or manuscript preparation.

Author contributions

LD and ZQ designed and performed experiments, analyzed results, wrote the manuscript, and ZQ is the corresponding author. ZL and JQ performed experiments. ZL, YC and EKF performed statistical analysis or provided critical input.

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Correspondence to Z Qin.

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Dai, L., Lin, Z., Qiao, J. et al. Ribonucleotide reductase represents a novel therapeutic target in primary effusion lymphoma. Oncogene 36, 5068–5074 (2017). https://doi.org/10.1038/onc.2017.122

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