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

Oncogene volume 24, pages 5525–5532 (2005)Cite this article

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 multiprotein 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.

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Acknowledgements

We wish to thank B Young for the AF10 cDNA and Guoliang Xi for sharing unpublished results. We are grateful to Renate Zimmermann for technical assistance, and Georg Fey for continuous support. This work was supported by DFG Grants SL27/6-2 and SFB473/D2 to RKS, NIH Grants CA78815 and CA92251 to JLH, and by a stipend of GRK592 to DTZ. RKS is a recipient of a Ria Freifrau-von-Fritsch Stiftung career development award.

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  1. Department of Genetics, University Erlangen, Staudtstrasse 5, Erlangen, 91058, Germany

    Deniz T Zeisig, Claudia B Bittner, Bernd B Zeisig, Maria-Paz García-Cuéllar & Robert K Slany

  2. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA

    Jay L Hess

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Correspondence to Robert K Slany.

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Zeisig, D., Bittner, C., Zeisig, B. et al. The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene 24, 5525–5532 (2005). https://doi.org/10.1038/sj.onc.1208699

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