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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 90-102 |
| Number of pages | 13 |
| Journal | Stem Cell Reports |
| Volume | 4 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 13 2015 |
Fingerprint
ASJC Scopus subject areas
- Biochemistry
- Cell Biology
- Developmental Biology
- Genetics
Cite this
Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling. / 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.
In: Stem Cell Reports, Vol. 4, No. 1, 13.01.2015, p. 90-102.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Oxymetholone therapy of fanconi anemia suppresses osteopontin transcription and induces hematopoietic stem cell cycling
AU - Zhang, Qing-Shuo
AU - Benedetti, Eric
AU - Deater, Matthew
AU - Schubert, Kathryn
AU - Major, Angela
AU - Pelz, Carl
AU - Impey, Soren
AU - Marquez-Loza, Laura
AU - Rathbun, R. Keaney
AU - Kato, Shigeaki
AU - Bagby, Grover C.
AU - Grompe, Markus
PY - 2015/1/13
Y1 - 2015/1/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84920849913&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84920849913&partnerID=8YFLogxK
U2 - 10.1016/j.stemcr.2014.10.014
DO - 10.1016/j.stemcr.2014.10.014
M3 - Article
C2 - 25434823
AN - SCOPUS:84920849913
VL - 4
SP - 90
EP - 102
JO - Stem Cell Reports
JF - Stem Cell Reports
SN - 2213-6711
IS - 1
ER -