Abstract
Leukemia-associated fusion proteins establish aberrant transcriptional programs, which result in the block of hematopoietic differentiation, a prominent feature of the leukemic phenotype. The dissection of the mechanisms of deregulated transcription by leukemia fusion proteins is therefore critical for the design of tailored antileukemic strategies, aimed at reestablishing the differentiation program of leukemic cells. The acute promyelocytic leukemia (APL)-associated fusion protein PML-retinoic acid receptor (RAR) behaves as an aberrant transcriptional repressor, due to its ability to induce chromatin modifications (histone deacetylation and DNA methylation) and silencing of PML-RAR target genes. Here, we indicate that the ultimate result of PML-RAR action is to impose a heterochromatin-like structure on its target genes, thereby establishing a permanent transcriptional silencing. This effect is mediated by the previously described association of PML-RAR with chromatin-modifying enzymes (histone deacetylases and DNA methyltransferases) and by recruitment of the histone methyltransferase SUV39H1, responsible for trimethylation of lysine 9 of histone H3.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation
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DNA Methylation
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Gene Silencing
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / metabolism*
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Histones / chemistry
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Histones / metabolism
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Humans
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Leukemia, Promyelocytic, Acute / genetics
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Leukemia, Promyelocytic, Acute / metabolism
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Leukemia, Promyelocytic, Acute / pathology
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Methylation
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Methyltransferases / genetics
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Methyltransferases / metabolism*
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Models, Biological
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Promyelocytic Leukemia Protein
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Protein Methyltransferases
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Repressor Proteins / genetics
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Repressor Proteins / metabolism*
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transfection
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / metabolism*
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U937 Cells
Substances
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Histones
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Neoplasm Proteins
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Nuclear Proteins
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Oncogene Proteins, Fusion
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Promyelocytic Leukemia Protein
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Repressor Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
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PML protein, human
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SUV39H1 protein, human
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Histone Methyltransferases
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Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase