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Blood, 1 November 2005, Vol. 106, No. 9, pp. 3134-3141. Prepublished online as a Blood First Edition Paper on July 26, 2005; DOI 10.1182/blood-2005-03-0972. This Article Full Text (PDF) All Versions of this Article: 2005-03-0972v1 106/9/3134    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Ohtsuka, Y. Articles by Tsuji, K. Search for Related Content PubMed PubMed Citation Articles by Ohtsuka, Y. Articles by Tsuji, K. Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 11, 2005 Accepted June 9, 2005 RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro Yoshitoshi Ohtsuka, Atsushi Manabe, Hirohide Kawasaki, Daisuke Hasegawa, Yuji Zaike, Sumiko Watanabe, Takakuni Tanizawa, Tatsutoshi Nakahata, and Kohichiro Tsuji* Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan; Hyogo College of Medicine, Nishinomiya, Japan Department of Pediatrics, St. Luke's International Hospital, Tokyo, Japan Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan Department of Pediatrics, Tokyo Medical University, Tokyo, Japan Department of Laboratory Medicine, Research Hospital, Institute of Medical Science, University of Tokyo, Tokyo, Japan Division of Molecular and Developmental Biology, Institute of Medical Science, University of Tokyo, Tokyo, Japan Hyogo College of Medicine, Nishinomiya, Japan Department of Pediatrics, Kyoto University, Kyoto, Japan * Corresponding author; email: tsujik{at}ims.u-tokyo.ac.jp. Juvenile myelomonocytic leukemia (JMML) is a clonal myeloproliferative/myelodysplastic disorder of early childhood with a poor prognosis. JMML cells are characterized by hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF) caused by a continuously activated GM-CSF receptor-RAS signal transduction pathway through various molecular mechanisms, resulting in spontaneous GM colony formation in vitro. Bisphosphonate zoledronic acid (ZOL), a RAS-blocking compound, suppressed colony formation from bone marrow (BM) cells of 8 JMML patients and 5 normal controls without and with GM-CSF (10 ng/mL), respectively, in a dose-dependent manner in clonal culture. At 10 µM of ZOL, however, spontaneous GM colony formation from JMML BM cells decreased to 3%, but the formation of G colonies containing granulocytes, but no macrophages, was enhanced, while 40% of GM colonies were retained and G colony formation was not affected in culture of normal BM cells with GM-CSF. In suspension culture, cytochemical and flow cytometric analyses showed that 10 µM of ZOL also inhibited spontaneous proliferation and differentiation along monocyte/macrophage lineage of JMML BM cells, but not the development of normal BM cells by GM-CSF. The inhibitory effect of ZOL on JMML cells was confirmed at a single-clone level, and observed even at 3 µM. The current result offers a novel approach to therapy in JMML. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: G. T. Stathopoulos, C. Moschos, H. Loutrari, A. Kollintza, I. Psallidas, S. Karabela, S. Magkouta, Z. Zhou, S. A. Papiris, C. Roussos, et al. Zoledronic Acid Is Effective against Experimental Malignant Pleural Effusion Am. J. Respir. Crit. Care Med., July 1, 2008; 178(1): 50 - 59. [Abstract] [Full Text] [PDF]

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