Abstract
RAR and AML1 transcription factors are found in leukemias as fusion proteins with PML and ETO, respectively. Association of PML-RAR and AML1-ETO with the nuclear corepressor (N-CoR)/histone deacetylase (HDAC) complex is required to block hematopoietic differentiation. We show that PML-RAR and AML1-ETO exist in vivo within high molecular weight (HMW) nuclear complexes, reflecting their oligomeric state. Oligomerization requires PML or ETO coiled-coil regions and is responsible for abnormal recruitment of N-CoR, transcriptional repression, and impaired differentiation of primary hematopoietic precursors. Fusion of RAR to a heterologous oligomerization domain recapitulated the properties of PML-RAR, indicating that oligomerization per se is sufficient to achieve transforming potential. These results show that oligomerization of a transcription factor, imposing an altered interaction with transcriptional coregulators, represents a novel mechanism of oncogenic activation.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Cell Transformation, Neoplastic*
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Core Binding Factor Alpha 2 Subunit
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Histone Deacetylases / metabolism
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Humans
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Leukemia / etiology
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Leukemia / genetics*
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Leukemia, Myeloid / etiology
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Leukemia, Myeloid / genetics
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Leukemia, Promyelocytic, Acute / etiology
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Leukemia, Promyelocytic, Acute / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / metabolism
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Nuclear Receptor Co-Repressor 1
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Oncogene Proteins, Fusion / metabolism*
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Peptide Fragments / 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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Repressor Proteins / metabolism
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Response Elements
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Transcription Factors / metabolism*
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Transcription, Genetic
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Tretinoin
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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NCOR1 protein, human
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Neoplasm Proteins
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Nuclear Proteins
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Nuclear Receptor Co-Repressor 1
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Oncogene Proteins, Fusion
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Peptide Fragments
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RUNX1 Translocation Partner 1 Protein
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Repressor Proteins
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Transcription Factors
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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Tretinoin
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Histone Deacetylases