Affiliation:
1. Department of Pathology, Stanford University School of Medicine, Stanford, California
Abstract
ABSTRACT
The
MLL
gene is a frequent target for leukemia-associated chromosomal translocations that generate dominant-acting chimeric oncoproteins. These invariably contain the amino-terminal 1,400 residues of
MLL
fused with one of a variety of over 30 distinct nuclear or cytoplasmic partner proteins. Despite the consistent inclusion of the
MLL
amino-terminal region in leukemia oncoproteins, little is known regarding its molecular contributions to
MLL
-dependent oncogenesis. Using high-resolution mutagenesis, we identified three MLL domains that are essential for in vitro myeloid transformation via mechanisms that do not compromise subnuclear localization. These include the CXXC/Basic domain and two novel domains of unknown function. Point mutations in the CXXC domain that eliminate myeloid transformation by an
MLL
fusion protein also abolished recognition and binding of nonmethylated CpG DNA sites in vitro and transactivation in vivo. Our results define a critical role for the CXXC DNA binding domain in
MLL
-associated oncogenesis, most likely via epigenetic recognition of CpG DNA sites within the regulatory elements of target genes.
Publisher
American Society for Microbiology
Subject
Cell Biology,Molecular Biology
Cited by
139 articles.
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