Induction of malignant transformation of cocultivated hematopoietic stem cells by X-irradiation of murine bone marrow stromal cells in vitro.
X-irradiation of purified primary cultures of mouse bone marrow stroma or permanent cloned marrow stromal cell lines in plateau phase decreases production of macrophage progenitor cell-specific colony-stimulating factor to a plateau minimum of 40% of control levels after doses of 50 to 500 Gy delivered at 2 Gy/min. After 50 Gy there is increased bioavailability of another growth factor(s) that is distinct from macrophage progenitor cell-specific colony-stimulating factor, granulocyte-macrophage progenitor cell colony-stimulating factor, or colony-stimulating factor for multipotential hematopoietic stem cells (interleukin 3). Liquid-phase cocultivation of irradiated stromal cells with either nonadherent cells from continuous marrow cultures or cloned dual granulocyte-macrophage progenitor cell colony-stimulating factor/interleukin 3-dependent hematopoietic progenitor cell lines induces evolution over 5 weeks of factor-independent colony-forming cells. Subcultured factor-independent colonies generated clonal malignant cell lines with multiple distinct karyotypic alterations. Inoculation of 10(6) cells s.c. from factor-independent clones into syngeneic mice produces local granulocytic monomyeloid tumors with spread to spleen, lymph nodes, and bone marrow. These data provide the first demonstration in vitro of indirect X-irradiation leukemogenesis through cells of the marrow stroma.
D000818:Animals; D001853:Bone Marrow / Q000528:radiation effects*; D001854:Bone Marrow Cells; D002471:Cell Transformation, Neoplastic / Q000473:pathology / Q000528:radiation effects*; D002478:Cells, Cultured; D003115:Colony-Stimulating Factors / Q000494:pharmacology; D006133:Growth Substances / Q000032:analysis; D006412:Hematopoietic Stem Cells / Q000473:pathology*; D066298:In Vitro Techniques; D007377:Interleukin-3; D007621:Karyotyping; D007953:Leukemia, Radiation-Induced / Q000209:etiology* / Q000473:pathology; D008222:Lymphokines / Q000494:pharmacology; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology; D014965:X-Rays
D003115:Colony-Stimulating Factors; D006133:Growth Substances; D007377:Interleukin-3; D008222:Lymphokines