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Animal Models

Development and analysis of patient-derived xenograft mouse models in intravascular large B-cell lymphoma

Leukemia volume 30, pages 1568–1579 (2016)Cite this article

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Abstract

Intravascular large B-cell lymphoma (IVLBCL) is a distinct disease entity with the peculiar characteristic that tumor cells proliferate within vessels. Despite recent advances in understanding the disease from clinical aspects, the underlying pathogenesis remains unknown. Here we demonstrate analyses of IVLBCL biology using four xenograft mouse models established from primary IVLBCL samples. In all four models, the main characteristic of IVLBCL tumor cell proliferation within vessels was retained. Time-lapse engraftment analyses revealed that the tumor cells initially engrafted and proliferated in the sinusoids and vessels in the liver and then engrafted and proliferated in multiple organs. Intriguingly, serial passage of tumor cells from the adrenal gland of a transplanted mouse developed from primary patient bone marrow cells into a second mouse showed that the tumor cells mainly distributed into the adrenal gland in the second mouse, implying the existence of clonal selection and/or evolution at engraftment of a specific organ. Gene expression profiling analyses demonstrated that the gene set associated with cell migration was enriched for normal peripheral blood B cells, indicating that inhibition of cell migration might be involved in IVLBCL pathogenesis. In conclusion, the mouse xenograft models described here are essential tools for uncovering IVLBCL biology.

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Acknowledgements

We thank Mr Kuniyoshi Kitou, Ms Kazuko Matsuba, Ms Yuko Katayama and Mr Yoshiaki Inagaki (Nagoya University) for immunohistochemistry work; Ms Asako Watanabe, Ms Yoko Matsuyama, Ms Chika Wakamatsu, Ms Manami Kira, Ms Rie Kojima, Ms Yukie Konishi, Ms Yuko Kojima and Ms Emi Kohno (Nagoya University) for assistance with laboratory work; Dr Seitaro Terakura (Nagoya University), Dr Kuniaki Kitamura and Dr Eri Iwata (Ichinomiya Municipal Hospital) for providing patient samples and information; Dr Tomoya Katakai (Niigata University) for providing the BLS4 cell line; Mr Toshiyuki Takeuchi (Oncomics Co. Ltd) for providing information regarding GEP analysis; and Ms Kyoko Hirano (Aichi Cancer Center) for assistance with the array CGH study. This work was supported by the Program to Disseminate Tenure Tracking System, MEXT, Japan, by a JSPS Grant-in-Aid for Young Scientists (B) 26860724, by the Practical Research for Innovative Cancer Control, MHLW/AMED, Japan, and by the Kanae Foundation for the Promotion of Medical Science grant to KS.

Author contributions

K Shimada, TN, FH, M Seto, AT and HK designed research; K Shimada, K Sugimoto, TT, YT, AS and TA established mouse models; K Shimada, SS, K Sugimoto and YT performed experiments; K Shimada, MN, M Suguro, AH, IT, SN and M Seto analyzed and interpreted data; K Shimada, MN, M Suguro, AH, TDH and IT performed statistical analysis; TN, SN, FH, M Seto, AT and HK supervised research; K Shimada, MN, M Suguro, AH, IT, M Seto, AT and HK wrote the manuscript; and all authors reviewed and revised the manuscript.

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Authors and Affiliations

  1. Institute for Advanced Research, Nagoya University, Nagoya, Japan

    K Shimada

  2. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    K Shimada, K Sugimoto, T Tokunaga, Y Takagi, A Sakamoto, T Aoki, T Naoe, F Hayakawa, A Tomita & H Kiyoi

  3. Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan

    S Shimada & S Nakamura

  4. Fujii Memorial Research Institute, Otsuka Pharmaceutical Co., Ltd, Otsu, Japan

    K Sugimoto

  5. Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Nagoya, Japan

    M Nakatochi & A Hirakawa

  6. Division of Molecular Medicine, Aichi Cancer Center Research Institute, Nagoya, Japan

    M Suguro & M Seto

  7. Department of Human Genetics, McGill University, Montreal, Quebec, Canada

    T D Hocking

  8. Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan

    I Takeuchi

  9. Department of Hematology, National Hospital Organization, Nagoya Medical Center, Nagoya, Japan

    T Tokunaga & T Naoe

  10. Department of Pathology, Kurume University School of Medicine, Kurume, Japan

    M Seto

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  1. K Shimada
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Correspondence to K Shimada.

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Competing interests

K Sugimoto is an employee of Otsuka Pharmaceutical Co., Ltd and M Seto is an employee of Immuno-Biological Laboratories Co., Ltd. TN received research funding from Astellas Pharma Inc., Celgene KK, Fujifilm Corporation, Kyowa-Hakko Kirin Co., Ltd, Nippon Boehringer Ingelheim Co., Ltd, Otsuka Pharmaceutical Co., Ltd, Pfizer Inc. and Toyoma Chemical Co., Ltd, has issued patents and royalties with Chugai Pharmaceutical Co., Ltd, and Kyowa-Hakko Kirin Co., Ltd and has pending patents and royalties with Fujifilm Corporation. HK has served as a consultant for Astellas Pharma Inc. and Kyowa-Hakko Kirin Co., Ltd and has received research funding from Fujifilm Corporation, Nippon Boehringer Ingelheim Co., Ltd, Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd, Kyowa-Hakko Kirin Co., Ltd, Zenyaku Kogyo Company Ltd, FUJIFILM RI Pharma Co., Ltd, Nippon Shinyaku Co., Ltd, the Japan Blood Products Organization, Astellas Pharma Inc., Eisai Co., Ltd, Yakult Honsha Co., Ltd, Pfizer Inc., Takeda Pharmaceutical Co., Ltd, MSD K.K., Alexion Pharmaceuticals, Teijin Ltd, Mochida Pharmaceutical Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Taisho Toyama Pharmaceutical Co., Ltd and Novartis Pharma K.K. and has patents and royalties with Fujifilm Corporation.

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Shimada, K., Shimada, S., Sugimoto, K. et al. Development and analysis of patient-derived xenograft mouse models in intravascular large B-cell lymphoma. Leukemia 30, 1568–1579 (2016). https://doi.org/10.1038/leu.2016.67

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