The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin

Deniz T. Zeisig, Claudia B. Bittner, Bernd B. Zeisig, Maria Paz García-Cuéllar, Jay L. Hess, Robert K. Slany

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Abstract

Mixed lineage leukemia (MLL) fusion proteins are derived from translocations at 11q23 that occur in aggressive subtypes of leukemia. As a consequence, MLL is joined to different unrelated proteins to form oncogenic transcription factors. Here we demonstrate a direct interaction between several nuclear MLL fusion partners and present evidence for a role of these proteins in histone binding. In two-hybrid studies, ENL interacted with AF4 and AF5q31 as well as with a fragment of AF10. A structure-function analysis revealed that the AF4/AF5q31/AF10 binding domain in ENL coincided with the C-terminus that is essential for transformation by MLL-ENL. The ENL/AF4 association was corroborated by GST-pulldown experiments and by mutual coprecipitation. Both proteins colocalized in vivo in a nuclear speckled pattern. Moreover, AF4 and ENL coeluted on sizing columns together with the known ENL binding partner Polycomb3, suggesting the presence of a multi-protein complex. The overexpression of ENL alone activated a reporter construct and a mutational screen indicated the conserved YEATS domain as essential for this function. Overlay and pulldown-assays finally showed a specific and YEATS domain-dependent association of ENL with histones H3 and H1. In summary, our studies support a common role for nuclear MLL fusion partners in chromatin biology.

Original languageEnglish (US)
Pages (from-to)5525-5532
Number of pages8
JournalOncogene
Volume24
Issue number35
DOIs
StatePublished - Aug 18 2005

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Keywords

  • Chromatin
  • ENL
  • Histone
  • Leukemia
  • MLL

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zeisig, D. T., Bittner, C. B., Zeisig, B. B., García-Cuéllar, M. P., Hess, J. L., & Slany, R. K. (2005). The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene, 24(35), 5525-5532. https://doi.org/10.1038/sj.onc.1208699