title: Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling.
abstract: 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.
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA. Electronic address: zhangqi@ohsu.edu.
authors.forename: Qing-Shuo
authors.initials: QS
authors.lastname: Zhang
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Benedetti
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Deater
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Schubert
authors.affiliation: Department of Pathology, Texas Children's Hospital, Houston, TX 77030, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Major
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: Pelz
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Soren
authors.initials: S
authors.lastname: Impey
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Marquez-Loza
authors.affiliation: NW VA Cancer Research Center, VA Medical Center Portland, Portland, OR 97239, USA.
authors.forename: R Keaney
authors.initials: RK
authors.lastname: Rathbun
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo 113-0032, Japan.
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.affiliation: NW VA Cancer Research Center, VA Medical Center Portland, Portland, OR 97239, USA.
authors.forename: Grover C
authors.initials: GC
authors.lastname: Bagby
authors.affiliation: Oregon Stem Cell Center, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97239, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Grompe
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001853:Bone Marrow / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects* / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005199:Fanconi Anemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000235:genetics; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000187:drug effects / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D053495:Osteopontin / Q000235:genetics*; D010110:Oxymetholone / Q000494:pharmacology* / Q000627:therapeutic use; D010198:Pancytopenia / Q000097:blood / Q000235:genetics / Q000473:pathology; D017423:Sequence Analysis, RNA; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects*
chemical_list: D052236:Fanconi Anemia Complementation Group D2 Protein; D053495:Osteopontin; D010110:Oxymetholone