Researchers Make Anemia Discovery That May Provide New Targets for Therapy

Researchers at the University of Virginia School of Medicine are have discovered an unknown clockwork mechanism within the body that controls the creation of red blood cells. Reporting in Journal of Experimental Medicine, they describe how iron restriction limits surface display of erythropoietin receptor in primary progenitors. Their experiments revealed that mice with enforced surface retention of the receptor failed to develop anemia with iron deprivation.

Adam Goldfarb, MD, from the department of pathology at the University of Virginia School of Medicine in Charlottesville, Virginia, and his colleagues made these discoveries while seeking to better understand why iron-restricted anemias result in insufficient red blood cell creation. Members of the research team were working independently on what would prove to be key pieces of the puzzle. The Scribble protein (named after the SCRIB gene that produces it) was found to be a key piece of the clockwork mechanism.

The current study revealed that the amount of iron in the blood affects the amount of the Scribble protein available.  In addition, Scribble appears to control whether the hormone receptor is welled up inside the bone marrow cells or doing its job on the outside. The team found that erythroid iron restriction down-regulates Scribble, which is a receptor control element. They write that this mechanistic pathway is mediated by the iron-sensing transferrin receptor, and that Scribble deficiency reduces surface expression of the erythropoietin receptor.

“We found that iron availability dictates surface levels of the erythropoietin receptor on bone marrow erythroid progenitors. This explains the resistance to erythropoietin treatment that occurs with iron deficiency. We also identified a molecular pathway by which iron regulates surface erythropoietin levels and identified that a simple metabolite isocitrate can act as a surrogate for iron and restore erythropoietin response,” Dr. Goldfarb told Cancer Network.

He said key elements of this pathway are the proteins transferrin receptor 2 (TfR2) and Scribble.  Dr. Goldfarb said these findings are relevant to anemias associated with chronic inflammation in which marrow erythroid progenitors also lose responsiveness to erythropoietin. “Our findings define a pathway that is amenable to pharmacologic targeting, offering new approaches to treat these anemias,” said Dr. Goldfarb.

Currently, the researchers are continuing to explore what the initial signals are that trigger changes in TfR2 and Scribble with iron deprivation. On a translational level, the researchers are trying to optimize the safety and efficacy of oral isocitrate treatment for anemia of inflammation using mouse model systems, Dr. Goldfarb noted.