Cited by 368Acute Myeloid Leukemia ResearchRetinoids in leukemia and cellular processesGenomics and Chromatin Dynamics

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The t(8;21) Fusion Protein Interferes with AML-1B-Dependent Transcriptional Activation

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Meyers, Shari, Lenny, Noel, Hiebert, Scott W.·1995·Molecular and Cellular Biology

DOI 10.1128/mcb.15.4.1974PMC PMC230424

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Abstract

The AML-1/CBF beta transcription factor complex is targeted by both the t(8;21) and the inv(16) chromosomal alterations, which are frequently observed in acute myelogenous leukemia. AML-1 is a site-specific DNA-binding protein that recognizes the enhancer core motif TGTGGT. The t(8;21) translocation fuses the first 177 amino acids of AML-1 to MTG8 (also known as ETO), generating a chimeric protein that retains the DNA-binding domain of AML-1. Analysis of endogenous AML-1 DNA-binding complexes suggested the presence of at least two AML-1 isoforms. Accordingly, we screened a human B-cell cDNA library and isolated a larger, potentially alternatively spliced, form of AML1, termed AML1B. AML-1B is a protein of 53 kDa that binds to a consensus AML-1-binding site and complexes with CBF beta. Subcellular fractionation experiments demonstrated that both AML-1 and AML-1/ETO are efficiently extracted from the nucleus under ionic conditions but that AML-1B is localized to a salt-resistant nuclear compartment. Analysis of the transcriptional activities of AML-1, AML-1B, and AML-1/ETO demonstrated that only AML-1B activates transcription from the T-cell receptor beta enhancer. Mixing experiments indicated that AML-1/ETO can efficiently block AML-1B-dependent transcriptional activation, suggesting that the t(8;21) translocation creates a dominant interfering protein.

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Authors: Meyers, S., Lenny, N., & Hiebert, S. W.
Affiliations: St. Jude Children's Research Hospital (US)
ORCID: Hiebert, Scott W.
Venue: Molecular and Cellular Biology
Publisher: Informa UK Limited
Published: 1995-04-01
Volume: 15
Issue: 4
Pages: 1974-1982
ISSN: 0270-7306 (ISSN-L)
1098-5549
DOI: 10.1128/mcb.15.4.1974
PMC: PMC230424
OpenAlex: W2113086962
Cited by: 368
References: 46
Citations by year: 2025: 1 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 2 · 2019: 3 · 2018: 4 · 2017: 3 · 2016: 5 · 2015: 8 · 2014: 4 · 2013: 11 · 2012: 3
FWCI: 18.34
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Molecular and Cellular Biology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: American Lebanese Syrian Associated Charities
National Institutes of Health
National Cancer Institute (R01CA064140, P30CA021765)
Topics: Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
Keywords: ETO, CBFβ, acute myeloid leukemia, transcriptional activation, alternative splicing, DNA-binding domain, nuclear localization, chromosomal translocation
MeSH terms: RUNX1 Translocation Partner 1 Protein, Amino Acid Sequence, Base Sequence, Cell Compartmentation, Cell Nucleus, Cloning, Molecular, DNA-Binding Proteins, Enhancer Elements, Genetic, Gene Expression Regulation, Molecular Sequence Data, Neoplasm Proteins, Protein Binding, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Transcription Factors, Transcription, Genetic, Leukemia, Myeloid, Acute, Transcriptional Activation, Consensus Sequence, Alternative Splicing, DNA, Complementary, Core Binding Factors, Core Binding Factor Alpha 2 Subunit

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The t(8;21) Fusion Protein Interferes with AML-1B-Dependent Transcriptional Activation

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