A Leukemia-Related Protein is a Master Editor of the "Histone Code"

Rearrangements of the mixed lineage leukemia gene, MLL, are associated with aggressive leukemias in both children and adults. Researchers at the University of Pennsylvania School of Medicine have found that one portion of the MLL protein is an enzyme that “edits” the so-called histone code, a series of modifications to proteins associated with DNA that influence how and when certain genes are turned on and off. Their findings are presented in the November issue of Molecular Cell.

When functioning properly, the MLL protein regulates the expression of Hox genes, which play a role in cell growth and development. In some leukemias MLL is rearranged so that the cells are unable to turn off Hox genes. The Penn investigators found that a portion of the MLL protein binds directly to the Hox genes and edits the histone code at these sites. A rearranged form of MLL that causes leukemia also upregulated Hox expression but with a different “code”. Presumably the differences in the pattern of histone modifications accounts for their deregulated expression in leukemia.

The histone code hypothesis was first outlined by Dr. C. David Allis and colleagues, of the University of Virginia Health System, a co-author on this paper. The theory, which rapidly is gaining acceptance, postulates that expression of certain regions of DNA is turned on and off by modifying portions of histone proteins or DNA. Modified histones and DNA attract the cell’s gene-reading machinery via specific interactions with these elements of the histone code.

According to Jay L. Hess MD, PhD, of Penn’s Department of Pathology and Laboratory Medicine and senior author of the study, these results underscore the importance of the histone code in developmental biology and disease. “Domains similar to those with histone modifying activity in MLL are found in other proteins implicated in human tumors including acute leukemia, lymphoma, and prostate cancer and probably have a similar function. What is encouraging is that proteins with enzymatic activity are good targets for drug development. These are definitely exciting times for cancer biologists.”

This study was supported by grants from the Leukemia and Lymphoma Society, the National Institutes of Health, the Natural Sciences and Engineering Research Council of Canada, and the Genetics Institute of the Canadian Institute for Health Research.

Co-authors of this study include Tom Milne, Denise Gibbs, and Mary Ellen Martin, of Penn, Scott D. Briggs and C. David Allis of the University of Virginia Health System, and Hugh Brock of the University of British Columbia.