Kansas City, Mo. (September 1, 2009) – The Stowers Institute’s Shilatifard Lab has made advancements in their effort to understand the origins of chromosomal translocations in patients with Mixed Lineage Leukemia (MLL). MLL is associated with a genetic error that causes a portion of one chromosome to break and fuse with another. Their most recent findings have been published online by Molecular and Cellular Biology.

     The team identified the functional targets for the MLL1 gene and demonstrated that fewer than two percent of genes in the mammalian genome require MLL1 for the methylation of the histone H3K4 at their promoters. Methylation is the addition of a methyl group to a histone and is one of the molecular changes that can alter the interaction between DNA and nuclear proteins in ways that ultimately affect the regulation of gene expression. They also discovered that the H3K4 methylation implemented by MLL1 influences transcriptional initiation and RNA polymerase II recruitment at these target genes.

     “MLL1 was considered as the major methylase of H3K4 in mammalian cells and, therefore, has been studied intensively,” said Pengfei Wang, Ph.D., Senior Research Associate and lead author on the publication. “Our preliminary studies demonstrated that MLL1 is not required for bulk H3K4 methylation. When we followed up on those findings, we learned that only a very few of the genes, mostly developmentally regulated genes, in the mammalian genome require MLL1 as their sole H3K4 methylase.”

     “Every step or link that we can identify and clarify of the normal function of MLL1 helps us to better understand how MLL translocations result in human leukemia,” said Ali Shilatifard, Ph.D., Investigator and senior author on the publication. “In collaboration with my colleague, Robb Krumlauf, in this work, we not only identified the functional targets of MLL1, but we also identified unknown regions within the mammalian genome that are modified by MLL1. Further exploration of these concepts by our laboratories should help us define new targets for the treatment of MLL1 translocation-based leukemia.”

     Additional contributing authors from the Stowers Institute include Chengqi Lin, Open University Student in the Shilatifard Lab; Edwin Smith, Ph.D., Research Scientist; Brian Sanderson, Senior Laboratory Manager; Min Wu, Ph.D., formerly a Postdoctoral Research Associate; Madelaine Gogol, Bioinformatics Programmer Analyst II; Tara Alexander, Ph.D., Senior Research Associate; Christopher Seidel, Ph.D., Research Advisor; Leanne Wiedemann, Ph.D., Staff Scientist; and Robb Krumlauf, Ph.D., Investigator. Kai Ge, Ph.D., and Hong Guo from NIDDK, National Institutes of Health, also contributed.

     Dr. Shilatifard joined the Stowers Institute in 2007 from the Saint Louis University School of Medicine. Learn more about his work at www.stowers.org/labs/ShilatifardLab.asp.

About the Stowers Institute for Medical Research
     Housed in a 600,000 square-foot state-of-the-art facility on a 10-acre campus in the heart of Kansas City, Missouri, the Stowers Institute for Medical Research conducts basic research on fundamental processes of cellular life. Through its commitment to collaborative research and the use of cutting-edge technology, the Institute seeks more effective means of preventing, treating, and curing disease. Jim and Virginia Stowers endowed the Institute with gifts totaling $2 billion. The endowment resides in a large cash reserve and in substantial ownership of American Century Investments, a privately held mutual fund company that represents exceptional value for the Institute’s future.