Abstract
MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation.
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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Animals
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Bone Marrow Cells / metabolism
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Cell Survival / physiology*
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Cell Transformation, Neoplastic / metabolism*
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Cells, Cultured
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Cricetinae
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Cricetulus
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DNA-Binding Proteins / metabolism*
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Dimerization
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Gene Expression Regulation, Leukemic
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Hematopoietic System / metabolism
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Hematopoietic System / pathology*
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Histone-Lysine N-Methyltransferase
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Homeodomain Proteins / metabolism
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Humans
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Mice
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Myeloid-Lymphoid Leukemia Protein
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Neoplasm Proteins / metabolism
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Oncogene Proteins, Fusion / metabolism*
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogenes*
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Retroviridae
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Trans-Activators / metabolism
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Transcription Factors*
Substances
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DNA-Binding Proteins
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HOXA7 protein, human
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Homeodomain Proteins
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Hoxa7 protein, mouse
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KMT2A protein, human
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MEIS1 protein, human
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Meis1 protein, mouse
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Myeloid Ecotropic Viral Integration Site 1 Protein
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Neoplasm Proteins
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Oncogene Proteins, Fusion
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Trans-Activators
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Transcription Factors
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Myeloid-Lymphoid Leukemia Protein
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Histone-Lysine N-Methyltransferase
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Kmt2a protein, mouse