title: The effect of iron overload and chelation on erythroid differentiation.
abstract: We investigated the mechanisms of hematopoietic disorders caused by iron overload and chelation, in particular, the inhibition of erythroblast differentiation. Murine c-kit(+) progenitor cells or human CD34(+) peripheral blood hematopoietic progenitors were differentiated in vitro to the erythroid lineage with free iron and/or an iron chelator. Under iron overload, formation of erythroid burst-forming unit colonies and differentiation to mature erythroblasts were significantly suppressed; these effects were canceled by iron chelation with deferoxamine (DFO). Moreover, excessive iron burden promoted apoptosis in immature erythroblasts by elevating intracellular reactive oxygen species (ROS). Interestingly, both DFO and a potent anti-oxidant agent reduced intracellular ROS levels and suppressed apoptosis, thus restoring differentiation to mature erythroblasts. Accordingly, intracellular ROS may represent a new therapeutic target in the treatment of iron overload.
authors.affiliation: Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Taoka
authors.forename: Keiki
authors.initials: K
authors.lastname: Kumano
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Nakamura
authors.forename: Masataka
authors.initials: M
authors.lastname: Hosoi
authors.forename: Susumu
authors.initials: S
authors.lastname: Goyama
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Imai
authors.forename: Akira
authors.initials: A
authors.lastname: Hangaishi
authors.forename: Mineo
authors.initials: M
authors.lastname: Kurokawa
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003676:Deferoxamine / Q000494:pharmacology*; D004900:Erythroblasts / Q000166:cytology / Q000187:drug effects; D041905:Erythroid Cells / Q000166:cytology / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects* / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019190:Iron Overload / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D018952:Antigens, CD34; D007502:Iron Chelating Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D003676:Deferoxamine