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PMID: 9724795 Published · ppublish English Journal Article

ETO, fusion partner in t(8;21) acute myeloid leukemia, represses transcription by interaction with the human N-CoR/mSin3/HDAC1 complex.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 95 ·No. 18 ·1998-09-01 ·Pages 10860-5

Wang J, Hoshino T, Redner RL, Kajigaya S, Liu JM

Abstract

The t(8;21) translocation between two genes known as AML1 and ETO is seen in approximately 12-15% of all acute myeloid leukemia (AML) and is the second-most-frequently observed nonrandom genetic alteration associated with AML. AML1 up-regulates a number of target genes critical to normal hematopoiesis, whereas the AML1/ETO fusion interferes with this trans-activation. We discovered that the fusion partner ETO binds to the human homolog of the murine nuclear receptor corepressor (N-CoR). The interaction is mediated by two unusual zinc finger motifs present at the carboxyl terminus of ETO. Human N-CoR (HuN-CoR), which we cloned and sequenced in its entirety, encodes a 2,440-amino acid polypeptide and has a central domain that binds ETO. N-CoR, mammalian Sin3 (mSin3A and B), and histone deacetylase 1 (HDAC1) form a complex that alters chromatin structure and mediates transcriptional repression by nuclear receptors and by a number of oncoregulatory proteins. We found that ETO, through its interaction with the N-CoR/mSin3/HDAC1 complex, is also a potent repressor of transcription. This observation provides a mechanism for how the AML1/ETO fusion may inhibit expression of AML1-responsive target genes and disturb normal hematopoiesis.

MeSH Terms
Acute Disease Amino Acid Sequence Base Sequence Chromosomes, Human, Pair 21 Chromosomes, Human, Pair 8 DNA Primers DNA-Binding Proteins/genetics,metabolism Histone Deacetylases/genetics,metabolism Humans Leukemia, Myeloid/genetics Molecular Sequence Data Nuclear Proteins/chemistry,metabolism Nuclear Receptor Co-Repressor 1 Protein Binding Proto-Oncogene Proteins RUNX1 Translocation Partner 1 Protein Repressor Proteins/chemistry,genetics,metabolism Saccharomyces cerevisiae Proteins Transcription Factors/genetics,metabolism Transcription, Genetic/genetics Translocation, Genetic
Chemicals
DNA Primers DNA-Binding Proteins NCOR1 protein, human Nuclear Proteins Nuclear Receptor Co-Repressor 1 Proto-Oncogene Proteins RUNX1 Translocation Partner 1 Protein RUNX1T1 protein, human Repressor Proteins SIN3 protein, S cerevisiae Saccharomyces cerevisiae Proteins Transcription Factors Histone Deacetylases
Authors & Affiliations
5 authors, click to expand affiliations / ORCID
Wang J
Hematology Branch, National Heart, Lung, and Blood Institute, Bethesda MD 20892, USA.
Hoshino T
Redner R L
Kajigaya S
Liu J M
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.95.18.10860
Published
1998-09-01
Pages
10860-5
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC27986
Subset
IM
Databases
GENBANK
AF044209
External Links
PubMed source DOI: 10.1073/pnas.95.18.10860 PMC Full Text View journal details
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