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Acute Leukemias

The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells

Leukemia volume 27, pages 1469–1478 (2013)Cite this article

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Abstract

HERV-K (human endogenous retrovirus type K) type 1-encoded Np9 is a tumor-specific biomarker, but its oncogenic role and targets in human leukemia remain elusive. We first identified Np9 as a potent viral oncogene in human leukemia. Silencing of Np9 inhibited the growth of myeloid and lymphoblastic leukemic cells, whereas expression of Np9 significantly promoted the growth of leukemia cells in vitro and in vivo. Np9 not only activated ERK, AKT and Notch1 pathways but also upregulated β-catenin essential for survival of leukemia stem cells. In human leukemia, Np9 protein level in leukemia patients was substantially higher than that in normal donors (56% vs 4.5%). Moreover, Np9 protein level was correlated with the number of leukemia stem/progenitor cells but not detected in normal CD34+ hematopoietic stem cells. In addition, Np9-positive samples highly expressed leukemia-specific pol-env polyprotein, env and transmembrane proteins as well as viral particles. Thus, the viral oncogene Np9 is a critical molecular switch of multiple signaling pathways regulating the growth of leukemia stem/progenitor cells. These findings open a new perspective to understand the etiology of human common leukemia and provide a novel target for treating leukemia.

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Acknowledgements

This work was supported, in part, by the National Natural Science Foundation of China (30672381, 30873095, 81070420 and 81270601), Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents and the Grants of the Natural Science Foundation of Zhejiang Province (Y206238, Y2080570 and Y2080210).

Author Contributions

TC, ZPM, YCG, XQW, FX, YG, XHX, JFT, HZ, XZZ, XXG, CVN, GBX, LSH, XHZ, YMF, JCW performed experiments; WDH and RZX designed the study and interpreted the results and wrote the paper; SZ, and JJ provided conceptual advice.

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Author notes

  1. T Chen, Z Meng and Y Gan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    T Chen, Y Gan, Y Gu, X Xu, J Tang, H Zhou, X Zhang, G Xu, L Huang, X Zhang & R Xu

  2. Cancer Institute, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China

    T Chen, Y Gan, F Xu, Y Fang, J Wu, S Zheng & R Xu

  3. Division of Gene Regulation and Drug Discovery, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA

    Z Meng, X Wang, Y Gu, C Van Ness & W Huang

  4. Zhejiang Academy of Medical Sciences, Hangzhou, China

    X Gan

  5. Hematology Institute, Zhejiang University, Hangzhou, China

    J Jin

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  1. T Chen
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Correspondence to W Huang or R Xu.

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Chen, T., Meng, Z., Gan, Y. et al. The viral oncogene Np9 acts as a critical molecular switch for co-activating β-catenin, ERK, Akt and Notch1 and promoting the growth of human leukemia stem/progenitor cells. Leukemia 27, 1469–1478 (2013). https://doi.org/10.1038/leu.2013.8

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