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Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells

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An Erratum to this article was published on 09 February 2017

Abstract

The poor prognosis of adults with B cell precursor acute lymphoblastic leukemia (BCP-ALL) is attributed to leukemia cells that are protected by the bone marrow (BM) microenvironment. In the present study, we explored the pharmacological targeting of mesenchymal stromal/stem cells in BM (BM-MSCs) to eliminate chemoresistant BCP-ALL cells. Human BCP-ALL cells (NALM-6 cells) that adhered to human BM-MSCs (NALM-6/Ad) were highly resistant to multiple anti-cancer drugs, and exhibited pro-survival characteristics, such as an enhanced Akt/Bcl-2 pathway and increased populations in the G0 and G2/S/M cell cycle stages. Bortezomib, a proteasome inhibitor, interfered with adhesion between BM-MSCs and NALM-6 cells and up-regulated the matricellular protein SPARC (secreted protein acidic and rich in cysteine) in BM-MSCs, thereby reducing the NALM-6/Ad population. Inhibition of SPARC expression in BM-MSCs using a small interfering RNA enhanced adhesion of NALM-6 cells. Conversely, recombinant SPARC protein interfered with adhesion of NALM-6 cells. These results suggest that SPARC disrupts adhesion between BM-MSCs and NALM-6 cells. Co-treatment with bortezomib and doxorubicin prolonged the survival of BCP-ALL xenograft mice, with a significant reduction of leukemia cells in BM. Our findings demonstrate that bortezomib contributes to the elimination of BCP-ALL cells through disruption of their adhesion to BM-MSCs, and offer a novel therapeutic strategy for BCP-ALL through targeting of BM-MSCs.

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Acknowledgements

We thank Ms. Yoko Nakagawa for excellent technical assistance.

Author information

Author notes

  1. Satoshi Yoshioka

    Present address: Department of Hematology, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan

Authors and Affiliations

  1. Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan

    Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Asumi Yokota, Hideyo Hirai & Taira Maekawa

  2. Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan

    Masaki Iwasa, Aya Fujishiro & Akira Andoh

  3. Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan

    Sumie Fujii & Noriko Sugino

  4. Department of Hematology, National Hospital Organization Himeji Medical Center, Hyogo, 670-8520, Japan

    Terutoshi Hishita

  5. Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan

    Tatsuo Ichinohe

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  1. Masaki Iwasa
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Correspondence to Yasuo Miura.

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Grants

This work was supported in part by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science, and Technology in Japan (#26293277 and #15K09453, Y.M. and T.I.; #16H00656, N.S.). This work was also supported in part by the Program of the network-type joint Usage/Research Disaster Medical Science of Hiroshima University, Nagasaki University, and Fukushima Medical University (Y.M., S.F., and T.I.), the Kyoto Prevention Medical Center (Y.M.), and the Takeda Science Foundation (Y.M.).

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The authors declare no conflict of interest.

Additional information

An erratum to this article is available at http://dx.doi.org/10.1007/s12185-017-2182-8.

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Iwasa, M., Miura, Y., Fujishiro, A. et al. Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells. Int J Hematol 105, 587–597 (2017). https://doi.org/10.1007/s12185-016-2169-x

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