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

2015-01-09 00:01:54

Cancer Prevention Research; 9 Jan 2015; DOI: 10.1158/1940-6207



Liliana R. Souza, Erica Silva, Elissa Calloway, Omer Kucuk, Michael Rossi, Morgan L. McLemore



Abstract



Granulocyte colony-stimulating factor (G-CSF) has been utilized 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). 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 have demonstrated in this study that chronic G-CSF treatment in mice results in expansion of the hematopoietic stem cell 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 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 attainable through dietary supplementation.



INTRODUCTION



Severe congenital neutropenia (SCN) is a rare, heritable disorder characterized by isolated neutropenia from birth. Prior to the clinical use of granulocyte colony-stimulating factor (G-CSF), individuals typically died before the age of 2 from overwhelming infections. With G-CSF treatment, SCN patients now routinely survive until adolescence or even adulthood. Unfortunately, a substantial number of SCN patients now develop myelodysplastic syndrome (MDS) and/or acute myeloid leukemia (AML). After 10 years of G-CSF treatment, the rate of MDS/AML in SCN patients is estimated to be 2-3% per year. The etiology of AML in SCN is not well defined. The initial hypothesis was that a molecular defect responsible for SCN predisposed individuals to AML. Since accumulating evidence has demonstrated that MDS/AML arises from hematopoietic stem cells (HSC), this hypothesis appears less likely as the most frequently mutated gene in SCN, ELA2, is not expressed in HSCs. Another hypothesis is that chronic G-CSF treatment promotes expansion of a malignant myeloid clone. This remains a concern as the risk of MDS and/or AML roughly correlates with lifetime cumulative dosage of G-CSF. Other researchers have suggested that G-CSF usage in certain settings may promote leukemic transformation. These studies are far from conclusive, as others have shown no increase in the risk of leukemic transformation and/or relapse with G-CSF therapy. In particular, a prospective study has shown that G-CSF usage did not increase the rate of relapse or decrease complete remission rates in AML. However, SCN is unique in its cumulative lifetime dosage of G-CSF. SCN patients typically receive G-CSF multiple times per week for life, as opposed to patients undergoing chemotherapy who may
receive a short term treatment.



G-CSF signals through the granulocyte colony-stimulating factor receptor (G-CSFR). The G-CSFR is a non-tyrosine kinase receptor that is present at low levels on HSCs. In mice, G-CSF treatment results in an increase in HSCs. It is possible that chronic G-CSF treatment results in HSC proliferation and acquisition of mutations. Several lines of evidence lend support to this hypothesis. First, acquisition of hyperproliferative mutations of the G-CSFR increases the risk of leukemic transformation. Second, it has been demonstrated that HSCs preferentially utilize error prone DNA repair pathways when entering cell cycle and chromosomal deletions are often seen not only in patients with SCN and AML, but also in patients with aplastic anemia treated with G-CSF.



In this manuscript we provide evidence that prolonged G-CSF treatment results in genomic instability in murine HSCs. In addition, we demonstrate that treatment with the soy isoflavone genistein lessens DNA damage. This effect is achieved by utilizing genistein at a dosage that can be easily attainable by dietary supplementation, suggesting that genistein may be an effective preventive agent for those patients who require prolonged G-CSF treatment.



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