HSC Weekly 2012-10-26
USC study uncovers molecular components of healthy immune system
By Marie Rippen and Ellin Kavanagh
Fatih M. Uckun, professor of pediatrics at the Keck School of Medicine of USC, is first author on a paper describing the findings of a multi-institutional study that revealed fundamental new insights about the development of a healthy immune system.
The report was published in the October issue of the Proceedings of the National Academy of Sciences. The study involved analysis of gene expression profiles of lymphocyte precursors from 1,104 patients with childhood leukemia.
Ikaros protein is the master regulator of a child’s immune system development. It controls the genes that cooperatively contribute to the architecture of a healthy immune system that protects the child against infections and is capable of detecting and destroying cancerous cells if and when they are produced. Malfunction of Ikaros has been linked to development of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a strong and sustained Ikaros activity is considered of paramount importance, but until now it was not known how its function could be strengthened to further decrease the odds of developing leukemia.
Stuart Siegel, director of the Children’s Center for Cancer and Blood Diseases, said, “ALL is the most common type of cancer in children, so understanding its pathogenesis is of the utmost importance. This finding also helps to provide new information on how ALL originates and progresses, thereby making new and more effective treatments possible.”
Uckun and his colleagues at The Saban Research Institute of Children’s Hospital Los Angeles, have discovered that the enzyme SYK kinase specifically modifies Ikaros by adding two phosphates to unique regulatory sites. This so-called “phosphorylation” markedly improves the interactions of Ikaros with sequence-specific DNA segments of its target genes and amplifies its ability to accurately and effectively orchestrate the development of the immune system. The team also developed new diagnostic tools for a rapid analysis of Ikaros function in the laboratory that—upon further validation and optimization—could help identify children at high risk for leukemia.
“The new insights provided by this comprehensive analysis of Ikaros regulation have the potential to lay the foundation for innovative strategies aimed at preventing childhood leukemia,” said Uckun, head of Translational Research in Leukemia and Lymphoma in the Children’s Center for Cancer.
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