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PMID: 15542854 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Binding to nonmethylated CpG DNA is essential for target recognition, transactivation, and myeloid transformation by an MLL oncoprotein.

Molecular and cellular biology ·Vol. 24 ·No. 23 ·2004-12-00 ·Pages 10470-8

Ayton PM, Chen EH, Cleary ML

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.

MeSH Terms
Amino Acid Motifs Amino Acid Sequence Animals Blotting, Western Bone Marrow Cells/cytology COS Cells Cell Line Cell Nucleus/metabolism Cell Transformation, Neoplastic CpG Islands Cytoplasm/metabolism DNA/chemistry,genetics DNA Methylation DNA-Binding Proteins/genetics,metabolism Gene Deletion Genes, Reporter Histone-Lysine N-Methyltransferase Humans Luciferases/metabolism Mice Microscopy, Fluorescence Models, Genetic Molecular Sequence Data Mutation Myeloid-Lymphoid Leukemia Protein Plasmids/metabolism Point Mutation Protein Binding Protein Structure, Tertiary Proto-Oncogenes/genetics Sequence Homology, Amino Acid Transcription Factors/genetics,metabolism Transcriptional Activation Translocation, Genetic
Chemicals
DNA-Binding Proteins KMT2A protein, human Transcription Factors Myeloid-Lymphoid Leukemia Protein DNA Luciferases Histone-Lysine N-Methyltransferase Kmt2a protein, mouse
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Ayton Paul M
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Chen Everett H
Cleary Michael L
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43 references, click to expand
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.23.10470-10478.2004
Published
2004-12-00
Pages
10470-8
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC529055
Subset
IM
Grants
NCI NIH HHS · R01 CA055029 · United States
NCI NIH HHS · T32 CA009151 · United States
NCI NIH HHS · 5T32-CA09151 · United States
NCI NIH HHS · CA55029 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.23.10470-10478.2004 PMC Full Text View journal details
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