Menin Critically Links MLL Proteins With LEDGF on Cancer-Associated Target Genes

Cancer Cell. 2008 Jul 8;14(1):36-46. doi: 10.1016/j.ccr.2008.05.003.

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

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Chromatin / metabolism
  • Chromatin Assembly and Disassembly
  • Gene Expression Regulation, Leukemic*
  • HeLa Cells
  • Histone Methyltransferases
  • Histone-Lysine N-Methyltransferase / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Leukemia / enzymology
  • Leukemia / genetics
  • Leukemia / metabolism*
  • Leukemia / pathology
  • Mice
  • Mice, Inbred C57BL
  • Multiple Endocrine Neoplasia Type 1 / genetics
  • Multiple Endocrine Neoplasia Type 1 / metabolism
  • Mutation
  • Myeloid Progenitor Cells / enzymology
  • Myeloid Progenitor Cells / metabolism*
  • Myeloid-Lymphoid Leukemia Protein / genetics
  • Myeloid-Lymphoid Leukemia Protein / metabolism*
  • Protein Binding
  • Protein Methyltransferases
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • Time Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transduction, Genetic
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*
  • U937 Cells

Substances

  • Adaptor Proteins, Signal Transducing
  • Chromatin
  • Homeodomain Proteins
  • KMT2A protein, human
  • MEN1 protein, human
  • PSIP1 protein, human
  • Proto-Oncogene Proteins
  • Transcription Factors
  • Tumor Suppressor Proteins
  • homeobox protein HOXA9
  • Myeloid-Lymphoid Leukemia Protein
  • Histone Methyltransferases
  • Protein Methyltransferases
  • Histone-Lysine N-Methyltransferase