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Function of molecular switch pinpointed in severe congenital neutropenia
Date:3/6/2008

CINCINNATI Researchers have for the first time cleared an important hurdle to clarifying the molecular mechanics behind Severe Congenital Neutropenia (SCN), a deadly disease characterized by a deficiency of neutrophils a type of mature white blood cell important to fighting infection and disease. A research team led by Cincinnati Childrens Hospital Medical Center reports in the March 14 Immunity the first evidence of how a specific genetic mutation found in humans with SCN blocks neutrophil development in mouse bone marrow cells.

The finding is expected to give researchers a way to more effectively study SCN, which puts children at increased risk of developing bacterial and fungal infections and acute myelogenous leukemia.

Our discovery that humans and mice have a shared pathway for the development of neutrophils should provide new avenues for understanding the molecular basis of SCN associated with other genetic mutations, said H. Leighton Grimes, Ph.D., a researcher in the Division of Immunology at Cincinnati Childrens and lead author of the study. Its important that we find clues for developing possible treatments to help children with this disease.

The research team studied a gene called Growth Factor Independent-1 (GFI1), which is expressed in bone marrow stem cells and known to help control the growth and differentiation of blood cells, including those that become neutrophils. When it works normally, GFI1 promotes the formation of neutrophils by blocking the development of macrophages, the default differentiation pathway. Specifically, GFI1 acts as a molecular switch to moderate the function of another gene, Colony Stimulating Factor-1 (CSF1), which tells marrow stem cells to form macrophage white blood cells instead of neutrophils. Dr. Grimes and his colleagues discovered that GFI1s ability to act as a rate-limiting molecular switch is compromised by a genetic error found in patients with SCN, a mutation known as GFI1N382S.
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Contact: Nick Miller
513-803-6035
Cincinnati Children's Hospital Medical Center
Source:Eurekalert

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