(Philadelphia,
PA) - 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.
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