Abstract
AML1/ETO is the chimeric protein resulting from the t(8;21) in acute myeloid leukemia. The Nervy homology 2 (NHR2) domain in ETO mediates oligomerization and AML1/ETO's interactions with ETO, MTGR1, and MTG16, and with the corepressor molecules mSin3A and HDAC1 and HDAC3. We solved the NHR2 domain structure and found it to be an alpha-helical tetramer. We show that oligomerization contributes to AML1/ETO's inhibition of granulocyte differentiation, is essential for its ability to enhance the clonogenic potential of primary mouse bone marrow cells, and affects AML1/ETO's activity on several endogenous genes. Oligomerization is also required for AML1/ETO's interactions with ETO, MTGR1, and MTG16, but not with other corepressor molecules.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Binding Sites
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Cells, Cultured
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Core Binding Factor Alpha 2 Subunit / chemistry*
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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Crystallography, X-Ray
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Gene Expression Regulation
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Humans
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Hydrophobic and Hydrophilic Interactions
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Male
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Molecular Sequence Data
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Mutation / genetics
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Oncogene Proteins, Fusion / chemistry*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Protein Binding
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Protein Structure, Quaternary
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RUNX1 Translocation Partner 1 Protein
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Sequence Alignment
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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RUNX1 Translocation Partner 1 Protein