title: Genistein protects hematopoietic stem cells against G-CSF-induced DNA damage.
abstract: Granulocyte colony-stimulating factor (G-CSF) has been used to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that the chronic use of G-CSF in certain conditions increases the risk of myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). The most striking example is in severe congenital neutropenia (SCN). Patients with SCN develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. Myelodysplastic syndrome and AML that arise in these settings are commonly associated with chromosomal deletions. We have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell (HSC) population. In addition, primitive hematopoietic progenitors from G-CSF-treated mice show evidence of DNA damage as demonstrated by an increase in double-strand breaks and recurrent chromosomal deletions. Concurrent treatment with genistein, a natural soy isoflavone, limits DNA damage in this population. The protective effect of genistein seems to be related to its preferential inhibition of G-CSF-induced proliferation of HSCs. Importantly, genistein does not impair G-CSF-induced proliferation of committed hematopoietic progenitors, nor diminishes neutrophil production. The protective effect of genistein was accomplished with plasma levels that are attainable through dietary supplementation.
authors.affiliation: Department of Hematology and Oncology, Winship Cancer Institute, Emory University, 1365C Clifton Road, Room C3078, Atlanta, GA 30322. lsouza@emory.edu.
authors.forename: Liliana R
authors.initials: LR
authors.lastname: Souza
authors.forename: Erica
authors.initials: E
authors.lastname: Silva
authors.forename: Elissa
authors.initials: E
authors.lastname: Calloway
authors.forename: Omer
authors.initials: O
authors.lastname: Kucuk
authors.forename: Michael
authors.initials: M
authors.lastname: Rossi
authors.forename: Morgan L
authors.initials: ML
authors.lastname: McLemore
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D043171:Chromosomal Instability / Q000187:drug effects; D019610:Cytoprotection / Q000187:drug effects* / Q000235:genetics; D004249:DNA Damage / Q000187:drug effects*; D019587:Dietary Supplements; D019833:Genistein / Q000494:pharmacology*; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D015470:Leukemia, Myeloid, Acute / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D009190:Myelodysplastic Syndromes / Q000517:prevention & control
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D019833:Genistein