Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling

Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old...

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Bibliographic Details
Published in:Stem cell reports 2015-01, Vol.4 (1), p.90-102
Main Authors: Zhang, Qing-Shuo, Benedetti, Eric, Deater, Matthew, Schubert, Kathryn, Major, Angela, Pelz, Carl, Impey, Soren, Marquez-Loza, Laura, Rathbun, R Keaney, Kato, Shigeaki, Bagby, Grover C, Grompe, Markus
Format: Article
Language:English
Subjects:
Animals
Blood Cell Count
Bone Marrow - pathology
Cell Cycle - drug effects
Cell Cycle - genetics
Cell Proliferation - drug effects
Disease Models, Animal
Fanconi Anemia - drug therapy
Fanconi Anemia - genetics
Fanconi Anemia - pathology
Fanconi Anemia Complementation Group D2 Protein - genetics
Gene Expression Regulation
Hematopoiesis - drug effects
Hematopoiesis - genetics
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - metabolism
Humans
Mice
Mice, Knockout
Osteopontin - genetics
Oxymetholone - pharmacology
Oxymetholone - therapeutic use
Pancytopenia - blood
Pancytopenia - genetics
Pancytopenia - pathology
Sequence Analysis, RNA
Time Factors
Transcription, Genetic - drug effects
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Summary:Androgens are widely used for treating Fanconi anemia (FA) and other human bone marrow failure syndromes, but their mode of action remains incompletely understood. Aged Fancd2(-/-) mice were used to assess the therapeutic efficacy of oxymetholone (OXM) and its mechanism of action. Eighteen-month-old Fancd2(-/-) mice recapitulated key human FA phenotypes, including reduced bone marrow cellularity, red cell macrocytosis, and peripheral pancytopenia. As in humans, chronic OXM treatment significantly improved these hematological parameters and stimulated the proliferation of hematopoietic stem and progenitor cells. RNA-Seq analysis implicated downregulation of osteopontin as an important potential mechanism for the drug's action. Consistent with the increased stem cell proliferation, competitive repopulation assays demonstrated that chronic OXM therapy eventually resulted in stem cell exhaustion. These results expand our knowledge of the regulation of hematopoietic stem cell proliferation and have direct clinical implications for the treatment of bone marrow failure.
ISSN:2213-6711
2213-6711
DOI:10.1016/j.stemcr.2014.10.014