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International Journal of Hematology
Published in: International Journal of Hematology 5/2017

01-05-2017 | Original Article

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

Authors: Masaki Iwasa, Yasuo Miura, Aya Fujishiro, Sumie Fujii, Noriko Sugino, Satoshi Yoshioka, Asumi Yokota, Terutoshi Hishita, Hideyo Hirai, Akira Andoh, Tatsuo Ichinohe, Taira Maekawa

Published in: International Journal of Hematology | Issue 5/2017

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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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Metadata
Title
Bortezomib interferes with adhesion of B cell precursor acute lymphoblastic leukemia cells through SPARC up-regulation in human bone marrow mesenchymal stromal/stem cells
Authors
Masaki Iwasa
Yasuo Miura
Aya Fujishiro
Sumie Fujii
Noriko Sugino
Satoshi Yoshioka
Asumi Yokota
Terutoshi Hishita
Hideyo Hirai
Akira Andoh
Tatsuo Ichinohe
Taira Maekawa
Publication date
01-05-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 5/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-016-2169-x

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