Genistein Protects Hematopoietic Stem Cells against G-CSF-Induced DNA Damage

Granulocyte colony-stimulating factor (G-CSF) has been utilized to treat neutropenia in various clinical settings. Although clearly beneficial, there are concerns that 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). SCN patients develop MDS/AML at a high rate that is directly correlated to the cumulative lifetime dosage of G-CSF. MDS and AML that arise in these settings are commonly associated with chromosomal deletions. We demonstrate that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell population. Furthermore, 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 appears to be related to its preferential inhibition of G-CSF–induced proliferation of hematopoietic stem cells. Importantly, genistein does not impair G-CSF–induced proliferation of committed hematopoietic progenitors, nor diminish neutrophil production. The protective effect of genistein was accomplished with plasma levels that are easily attainable through dietary supplementation. aCGH was performed using NimbleGen DNA was extracted from bone marrow samples from mice treated with G-CSF or diluent for 4 months and analyzed using NimbleGen 3x720K mouse copy number arrays