Abstract
Rearrangements involving the NUP98 gene resulting in fusions to several partner genes occur in acute myeloid leukemia and myelodysplastic syndromes. This study demonstrates that the second FG repeat domain of the NUP98 moiety of the NUP98-HOXA9 fusion protein is important for its cell immortalization and leukemogenesis activities. We demonstrate that NUP98-HOXA9 interacts with mixed lineage leukemia (MLL) via this FG repeat domain and that, in the absence of MLL, NUP98-HOXA9-induced cell immortalization and leukemogenesis are severely inhibited. Molecular analyses indicate that MLL is important for the recruitment of NUP98-HOXA9 to the HOXA locus and for NUP98-HOXA9-induced HOXA gene expression. Our data indicate that MLL is crucial for NUP98-HOXA9 leukemia initiation.
MeSH terms
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Animals
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Cell Transformation, Neoplastic / genetics*
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Chromatin Immunoprecipitation
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Gene Expression Regulation, Leukemic / genetics*
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Histone-Lysine N-Methyltransferase / deficiency
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Histone-Lysine N-Methyltransferase / genetics
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Histone-Lysine N-Methyltransferase / physiology*
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Homeodomain Proteins / biosynthesis
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Homeodomain Proteins / chemistry
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Homeodomain Proteins / genetics
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Homeodomain Proteins / physiology*
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Humans
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Leukemia, Experimental / etiology
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Leukemia, Experimental / genetics*
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutagenesis, Site-Directed
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Myeloid-Lymphoid Leukemia Protein / deficiency
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / physiology*
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Nuclear Pore Complex Proteins / chemistry
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Nuclear Pore Complex Proteins / genetics
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Nuclear Pore Complex Proteins / physiology*
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Oncogene Proteins, Fusion / chemistry
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / physiology*
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Protein Binding
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Protein Domains
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Protein Interaction Mapping
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Radiation Chimera
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Transfection
Substances
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Homeodomain Proteins
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Myeloid Ecotropic Viral Integration Site 1 Protein
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NUP98-HOXA9 fusion protein, human
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Neoplasm Proteins
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Nuclear Pore Complex Proteins
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Oncogene Proteins, Fusion
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Myeloid-Lymphoid Leukemia Protein
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HoxA protein
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Histone-Lysine N-Methyltransferase
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Kmt2a protein, mouse