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.
Highlights
Severe congenital neutropenia (SCN) is a rare, heritable disorder characterized by isolated neutropenia from birth [1]
Because accumulating evidence has demonstrated that myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) arises from hematopoietic stem cells (HSC), this hypothesis seems less likely as the most frequently mutated gene in SCN, ELA2, is Authors' Affiliations: Departments of 1Hematology and Oncology and 2Radiology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
We hypothesized that excessive HSC proliferation induced by granulocyte colony-stimulating factor (G-CSF) could lead to deleterious consequences
Summary
Severe congenital neutropenia (SCN) is a rare, heritable disorder characterized by isolated neutropenia from birth [1]. With G-CSF treatment, patients with SCN routinely survive until adolescence or even adulthood. A substantial number of patients with SCN develop myelodysplastic syndrome (MDS) and/or acute myeloid leukemia After 10 years of G-CSF treatment, the rate of MDS/AML in patients with SCN is estimated to be 2% to 3% per year [2]. 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. Because accumulating evidence has demonstrated that MDS/AML arises from hematopoietic stem cells (HSC), this hypothesis seems less likely as the most frequently mutated gene in SCN, ELA2, is Authors' Affiliations: Departments of 1Hematology and Oncology and 2Radiology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia
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