Abstract
Menin displays the unique ability to either promote oncogenic function in the hematopoietic lineage or suppress tumorigenesis in the endocrine lineage; however, its molecular mechanism of action has not been defined. We demonstrate here that these discordant functions are unified by menin's ability to serve as a molecular adaptor that physically links the MLL (mixed-lineage leukemia) histone methyltransferase with LEDGF (lens epithelium-derived growth factor), a chromatin-associated protein previously implicated in leukemia, autoimmunity, and HIV-1 pathogenesis. LEDGF is required for both MLL-dependent transcription and leukemic transformation. Conversely, a subset of menin mutations in multiple endocrine neoplasia type 1 patients abrogate interaction with LEDGF while preserving MLL interaction but nevertheless compromise MLL/menin-dependent functions. Thus, LEDGF critically associates with MLL and menin at the nexus of transcriptional pathways that are recurrently targeted in diverse diseases.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Transformation, Neoplastic / genetics
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Cell Transformation, Neoplastic / metabolism*
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Cell Transformation, Neoplastic / pathology
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Chromatin / metabolism
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Chromatin Assembly and Disassembly
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Gene Expression Regulation, Leukemic*
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HeLa Cells
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Histone Methyltransferases
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Histone-Lysine N-Methyltransferase / metabolism
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Leukemia / enzymology
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Leukemia / genetics
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Leukemia / metabolism*
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Leukemia / pathology
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Mice
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Mice, Inbred C57BL
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Multiple Endocrine Neoplasia Type 1 / genetics
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Multiple Endocrine Neoplasia Type 1 / metabolism
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Mutation
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Myeloid Progenitor Cells / enzymology
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Myeloid Progenitor Cells / metabolism*
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Myeloid-Lymphoid Leukemia Protein / genetics
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Protein Binding
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Protein Methyltransferases
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism*
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RNA Interference
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Time Factors
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transduction, Genetic
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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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Adaptor Proteins, Signal Transducing
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Chromatin
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Homeodomain Proteins
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KMT2A protein, human
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MEN1 protein, human
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PSIP1 protein, human
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Proto-Oncogene Proteins
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Transcription Factors
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Tumor Suppressor Proteins
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homeobox protein HOXA9
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Myeloid-Lymphoid Leukemia Protein
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Histone Methyltransferases
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Protein Methyltransferases
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Histone-Lysine N-Methyltransferase