title: RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro.
abstract: 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-retrovirus-associated sequence (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 patients with JMML and 5 healthy control subjects without and with GM-CSF (10 ng/mL), respectively, in a dose-dependent manner in clonal culture. At 10 microM 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, whereas 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 microM 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 microM. The current result offers a novel approach to therapy in JMML.
authors.affiliation: Division of Cellular Therapy, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.
authors.forename: Yoshitoshi
authors.initials: Y
authors.lastname: Ohtsuka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Manabe
authors.forename: Hirohide
authors.initials: H
authors.lastname: Kawasaki
authors.forename: Daisuke
authors.initials: D
authors.lastname: Hasegawa
authors.forename: Yuji
authors.initials: Y
authors.lastname: Zaike
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
authors.forename: Takakuni
authors.initials: T
authors.lastname: Tanizawa
authors.forename: Tatsutoshi
authors.initials: T
authors.lastname: Nakahata
authors.forename: Kohichiro
authors.initials: K
authors.lastname: Tsuji
mesh_terms: D000293:Adolescent; D001853:Bone Marrow / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D015479:Leukemia, Myelomonocytic, Acute / Q000378:metabolism / Q000473:pathology*; D015477:Leukemia, Myelomonocytic, Chronic / Q000378:metabolism / Q000473:pathology*; D010710:Phosphates / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D000077211:Zoledronic Acid; D018631:ras Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D004164:Diphosphonates; D007093:Imidazoles; D010710:Phosphates; D000077211:Zoledronic Acid; D018631:ras Proteins