title: Oxidative stress leads to increased mutation frequency in a murine model of myelodysplastic syndrome.
abstract: The myelodysplastic syndromes (MDS) are characterized by ineffective hematopoiesis, dysplasia, and transformation to acute myeloid leukemia (AML). Although it has been suggested that additional mutations lead to progression of MDS to AML, the causative agent(s) for such mutations remains unclear. Oxidative stress is a potential cause, therefore, we evaluated levels of reactive oxygen species (ROS) in NUP98-HOXD13 (NHD13) transgenic mice, a murine model for MDS. Increased levels of ROS were detected in bone marrow nucleated cells (BMNC) that express CD71, a marker for cell proliferation, as well as immature, lineage negative bone marrow nucleated cells from NHD13 mice. In addition to the increase in ROS, increased DNA double strand breaks and activation of a G2/M phase cell cycle checkpoint were noted in NHD13 BMNC. Finally, using an in vivo assay for mutation frequency, we detected an increased mutation frequency in NHD13 BMNC. These results suggest that oxidative stress may contribute to disease progression of MDS to AML through ineffective repair of DNA damage and acquisition of oncogenic mutations.
authors: Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
authors: Yang Jo
authors: YJ
authors: Chung
authors: Department of Radiation Oncology and Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: Carine
authors: C
authors: Robert
authors: Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA.
authors: Sheryl M
authors: SM
authors: Gough
authors: Department of Radiation Oncology and Marlene & Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors: Feyruz V
authors: FV
authors: Rassool
authors: Genetics Branch, Center for Cancer Research, NCI, NIH, Bethesda, MD, USA. Electronic address: aplanp@mail.nih.gov.
authors: Peter D
authors: PD
authors: Aplan
mesh_terms: D000208:Acute Disease; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001854:Bone Marrow Cells / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D053903:DNA Breaks, Double-Stranded; D004195:Disease Models, Animal; D005434:Flow Cytometry; D059565:G2 Phase Cell Cycle Checkpoints / Q000235:genetics; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D059645:Mutation Rate; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000378:metabolism; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D015703:Antigens, CD; C068126:CD71 antigen; C470262:NUP98-HOXC13 fusion protein, human; D015514:Oncogene Proteins, Fusion; D017382:Reactive Oxygen Species; D011990:Receptors, Transferrin
keywords: AML; Big Blue(®) mice; MDS; Mutation; NHD13; ROS
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