Structural and functional analysis of the DOT1L-AF10 complex reveals mechanistic insights into MLL-AF10-associated leukemogenesis

Genes Dev. 2018 Mar 1;32(5-6):341-346. doi: 10.1101/gad.311639.118. Epub 2018 Mar 21.

Abstract

The mixed-lineage leukemia (MLL)-AF10 fusion oncoprotein recruits DOT1L to the homeobox A (HOXA) gene cluster through its octapeptide motif leucine zipper (OM-LZ), thereby inducing and maintaining the MLL-AF10-associated leukemogenesis. However, the recognition mechanism between DOT1L and MLL-AF10 is unclear. Here, we present the crystal structures of both apo AF10OM-LZ and its complex with the coiled-coil domain of DOT1L. Disruption of the DOT1L-AF10 interface abrogates MLL-AF10-associated leukemic transformation. We further show that zinc stabilizes the DOT1L-AF10 complex and may be involved in the regulation of the HOXA gene expression. Our studies may also pave the way for the rational design of therapeutic drugs against MLL-rearranged leukemia.

Keywords: DOT1L; MLL-AF10; crystal structure; leukemogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Transformation, Neoplastic / pathology*
  • Crystallization
  • Gene Expression Regulation, Neoplastic
  • Histone-Lysine N-Methyltransferase
  • Homeodomain Proteins / genetics
  • Humans
  • Methyltransferases* / chemistry
  • Methyltransferases* / metabolism
  • Models, Molecular*
  • Myeloid-Lymphoid Leukemia Protein* / chemistry
  • Myeloid-Lymphoid Leukemia Protein* / metabolism
  • Protein Binding
  • Protein Domains
  • Protein Structure, Quaternary
  • Structure-Activity Relationship
  • Transcription Factors* / chemistry
  • Transcription Factors* / metabolism
  • Zinc / chemistry

Substances

  • Homeodomain Proteins
  • MLLT10 protein, human
  • Transcription Factors
  • Myeloid-Lymphoid Leukemia Protein
  • HoxA protein
  • DOT1L protein, human
  • Methyltransferases
  • Histone-Lysine N-Methyltransferase
  • Zinc