Abstract
Rearrangements of the mixed lineage leukemia gene MLL are associated with aggressive lymphoid and myeloid leukemias. The resulting MLL fusion proteins enforce high-level expression of HOX genes and the HOX cofactor MEIS1, which is pivotal for leukemogenesis. Both wild-type MLL and MLL fusion proteins interact with the tumor suppressor menin and with the Hoxa9 locus in vivo. Here, we show that MLL sequences between amino acids 5 and 44 are required for interaction with menin and for the transformation of hematopoietic progenitors. Blocking the MLL-menin interaction by the expression of a dominant negative inhibitor composed of amino terminal MLL sequences down-regulates Meis1 expression and inhibits cell proliferation, suggesting that targeting this interaction may be an effective therapeutic strategy for leukemias with MLL rearrangements.
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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Cell Proliferation
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Cell Transformation, Neoplastic*
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Cells, Cultured
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Chromatin Immunoprecipitation
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Down-Regulation
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Gene Expression
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Histone-Lysine N-Methyltransferase
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism
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Humans
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Immunoprecipitation
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Kidney / embryology
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Leukemia, Myeloid / metabolism*
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Myeloid-Lymphoid Leukemia Protein / metabolism*
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism
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Polymerase Chain Reaction
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Proto-Oncogene Proteins / metabolism*
Substances
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Homeodomain Proteins
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KMT2A protein, human
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MEIS1 protein, human
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MEN1 protein, human
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins
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Proto-Oncogene Proteins
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase