1. RAS-blocking bisphosphonate zoledronic acid inhibits the abnormal proliferation and differentiation of juvenile myelomonocytic leukemia cells in vitro
- Author
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Yoshitoshi Ohtsuka, Tatsutoshi Nakahata, Takakuni Tanizawa, Kohichiro Tsuji, Daisuke Hasegawa, Yuji Zaike, Atsushi Manabe, Hirohide Kawasaki, and Sumiko Watanabe
- Subjects
medicine.medical_specialty ,Adolescent ,Cellular differentiation ,Immunology ,Biology ,Zoledronic Acid ,Biochemistry ,Leukemia, Myelomonocytic, Acute ,Phosphates ,Bone Marrow ,Internal medicine ,Tumor Cells, Cultured ,medicine ,Humans ,Macrophage ,Cell Proliferation ,Diphosphonates ,Juvenile myelomonocytic leukemia ,Cell growth ,Monocyte ,Imidazoles ,Cell Differentiation ,Leukemia, Myelomonocytic, Chronic ,Cell Biology ,Hematology ,Flow Cytometry ,medicine.disease ,Molecular biology ,In vitro ,Granulocyte macrophage colony-stimulating factor ,Endocrinology ,medicine.anatomical_structure ,ras Proteins ,Bone marrow ,medicine.drug - 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.
- Published
- 2005