Nelson J. Chao, MD, MBA
Dr. Chao indicated no relevant conflicts of interest.
Callens C, Coulon S, Naudin J, et al. Targeting iron homeostasis induces cellular differentiation and synergizes with differentiating agents in acute myeloid leukemia. J Exp Med. 2010;207:731-750.
The iron age, which began in Asia and Greece before migrating to Europe in 8th century B.C., ushered in significant changes in society when cutting tools and weapons were made with iron or steel. Besides its importance in tools and weapons, iron is essential to life in nearly all organisms. In cells, iron exists in the ferrous (Fe2+) and ferric (Fe3+) states that participate in the generation of reactive oxygen species and is stored in metalloproteins, since free iron can lead to production of toxic free radicals. In our bodies, iron is incorporated into the heme complex, specifically in special carrier proteins such as hemoglobin or myoglobin, and it is also required as a cofactor for critical cellular enzymes involved in metabolism and proliferation.
Because of problems associated with free radical generation, iron is tightly regulated through transferrin, which binds to iron as it is absorbed in the duodenum. The transferrin receptor (TR) is evolutionarily conserved and is a validated target for cancer therapy. Targeting TR in cancer cells would lead to iron depletion and therefore cell death. Earlier studies have suggested that iron chelators could be used as cancer therapies. In this paper, Callens et al. from the laboratories of Ivan Moura and Olivier Hermine in Paris, suggest that iron homeostasis is a good target in AML. They begin with the demonstration that iron chelation inhibits proliferation and induces monocyte differentiation in HL60 cells, and that 30 percent of the genes most strongly induced by iron deprivation were also targets of vitamin D3, a known differentiation agent. They demonstrated that iron chelation induced expression and phosphorylation of the vitamin D3 receptor and that the combination of iron chelation and vitamin D3 acted in a synergistic fashion. They then demonstrated the same effect with fresh AML blasts and showed induction of differentiation of the cells by measuring an increase in CD11b and CD14 expression. Furthermore, they demonstrated a similar drive to differentiation into monocytes with CD34+ cord blood progenitors. Mechanistically, the differentiation was felt to be through modulation of reactive oxygen species expression and the activation of mitogen-activated protein kinases (MAPKs). Finally, they treated a single patient with recurrent AML with the iron chelator desferoxamine and the vitamin D metabolite hydroxycholecalciferol. The patient showed a partial reversion of pancytopenia accompanied by an increase in monocyte numbers. The normal-appearing monocytes, but not lymphocytes or NK cells from the treated patient, contained the same trisomy 8 present in the original blasts.
These data suggest that the availability of iron may be important, especially in diseases such as AML that have a very high turnover of cells. The sequential events of iron deprivation, MAPK activation, and amplification of vitamin D receptor expression and phosphorylation lead to monocyte differentiation in malignant and normal precursor cells. These schema alone or combined with other differentiation agents could prove to be an important advance in the treatment of patients with AML.
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