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ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway

Oncogene volume 35, pages 3227–3238 (2016)Cite this article

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Abstract

ZFP521 was previously identified as a putative gene involved in induction of B-cell lymphomagenesis. However, the contribution of ZFP521 to lymphomagenesis has not been confirmed. In this study, we sought to elucidate the role of ZFP521 in B-cell lymphomagenesis. To this end, we used a retroviral insertion method to show that ZFP521 was a target of mutagenesis in pre-B-lymphoblastic lymphoma cells. The pre-B-cell receptor (pre-BCR) signaling molecules BLNK, BTK and BANK1 were positively regulated by the ZFP521 gene, leading to enhancement of the pre-BCR signaling pathway. In addition, c-myc and c-jun were upregulated following activation of ZFP521. Stimulation of pre-BCR signaling using anti-Vpreb antibodies caused aberrant upregulation of c-myc and c-jun and of Ccnd3, which encodes cyclin D3, thereby inducing the growth of pre-B cells. Stimulation with Vpreb affected the growth of pre-B cells, and addition of interleukin (IL)-7 receptor exerted competitive effects on pre-B-cell growth. Knockdown of BTK and BANK1, targets of ZFP521, suppressed the effects of Vpreb stimulation on cell growth. Furthermore, in human lymphoblastic lymphoma, analogous to pre-B-cell lymphoma in mice, the expression of ZNF521, the homolog of ZFP521 in humans, was upregulated. In conclusion, our data showed that the ZFP521 gene comprehensively induced pre-B-cell lymphomagenesis by modulating the pre-B-cell receptor signaling pathway.

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Acknowledgements

This work was supported by a Grant-in-Aid for Scientific Research on Innovative Areas, MEXT, Japan. Project name is ‘Synergy of fluctuation and Structure’. Significance statement: ZFP521 regulates pre-B-cell receptor-related genes and enhances pre-B-cell growth through the pre-B-cell receptor.

Author contributions

YT, RO, YI, TH and TT performed experiments. KT and TN provided materials. TT, YT and RO wrote the manuscript.

Disclaimer

This funding agency had no role in the study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article.

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Author notes

  1. T Hiratsuka, Y Takei and R Ohmori: These authors contributed equally to this work

Authors and Affiliations

  1. Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    T Hiratsuka

  2. Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan

    Y Takei, H Haga & T Tsuruyama

  3. Center for Anatomical, Pathological, and Forensic Medical Research, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    R Ohmori & T Tsuruyama

  4. Department of Forensic Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Y Imai, M Ozeki & K Tamaki

  5. Cancer Institute, Laboratory of Carcinogenesis, Tokyo, Japan

    T Nakamura

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Correspondence to T Tsuruyama.

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Hiratsuka, T., Takei, Y., Ohmori, R. et al. ZFP521 contributes to pre-B-cell lymphomagenesis through modulation of the pre-B-cell receptor signaling pathway. Oncogene 35, 3227–3238 (2016). https://doi.org/10.1038/onc.2015.385

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