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.
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.
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Iwasa
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. ym58f5@kuhp.kyoto-u.ac.jp.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miura
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Fujishiro
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Sumie
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, 606-8507, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Sugino
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.|Department of Hematology, Kobe City Medical Center General Hospital, Kobe, 650-0047, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yoshioka
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Yokota
authors.affiliation: Department of Hematology, National Hospital Organization Himeji Medical Center, Hyogo, 670-8520, Japan.
authors.forename: Terutoshi
authors.initials: T
authors.lastname: Hishita
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hideyo
authors.initials: H
authors.lastname: Hirai
authors.affiliation: Department of Medicine, Shiga University of Medical Science, Shiga, 520-2192, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Andoh
authors.affiliation: Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, 734-8553, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Ichinohe
authors.affiliation: Department of Transfusion Medicine and Cell Therapy, Kyoto University Hospital, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Taira
authors.initials: T
authors.lastname: Maekawa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001402:B-Lymphocytes / Q000473:pathology*; D001854:Bone Marrow Cells; D000069286:Bortezomib / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells; D016513:Mice, SCID; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000473:pathology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015676:Osteonectin; C577241:SPARC protein, human; D000069286:Bortezomib
keywords: Anti-adhesion molecule; B cell precursor acute lymphoblastic leukemia; Bortezomib; Human bone marrow mesenchymal stromal/stem cell; SPARC