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Acute Leukemias

Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75)

Leukemia volume 27, pages 1245–1253 (2013)Cite this article

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Abstract

The lens epithelium-derived growth factor (LEDGF/p75) tethers the mixed-lineage leukemia (MLL1) protein complex to chromatin. Likewise, LEDGF/p75 tethers the HIV-1 pre-integration complex to chromatin. We previously demonstrated that expression of the C-terminal fragment fused to enhanced green fluorescent protein (eGFP) (eGFP-LEDGF325–530) impaired HIV-1 replication. Here, we explored this strategy to selectively interfere with the leukemogenic activity of MLL-fusion proteins. We found that expression of LEDGF325–530 impaired the clonogenic growth of MLL-fusion gene transformed human and mouse hematopoietic cells, without affecting the growth of control cells immortalized by the FLT3-ITD mutant or normal lineage-marker-depleted murine bone marrow cells. Expression of LEDGF325–530 was associated with downregulation of the MLL target Hoxa9 and impaired cell cycle progression. Structure-function analysis revealed two small eGFP-fused LEDGF/p75 peptides, LEDGF424–435 and LEDGF375–386 phenocopying these effects. Both LEDGF325–530 and the smaller active peptides were able to disrupt the LEDGF/p75–MLL interaction. Expression of LEDGF325–530 or LEDGF375–386 fragments increased the latency period to disease development in vivo in a mouse bone marrow transplant model of MLL–AF9-induced AML. We conclude that small peptides disrupting the LEDGF/p75–MLL interface have selective anti-leukemic activity providing a direct rationale for the design of small molecule inhibitors targeting this interaction.

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Acknowledgements

We would like to thank A Tzankov, E Traunecker, T Krebs and U Schneider (Basel) and M Michiels and NJ Vanderveken (Leuven) for their help during this project. This work was supported by the Gertrude Von Meissner Foundation, the Swiss National Science Foundation (SNF-31003A-130661/1), the Swiss Cancer League (KFS-02778-02-2011), the Krebsliga beider Basel (Susy Rückert Foundation, Nr. 03-2011), and the Swiss Bridge Award to JS; and the agency for Innovation by Science and Technology (IWT), Flanders (SBO Interactomics), and the Research Foundation Flanders (FWO), Flanders (KAN2012 1.5.108.12) to ZD, KC and JD are supported by the FWO. FC is a KU Leuven Industrial Research Fund fellow.

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Author notes

  1. H Méreau and J De Rijck: These authors contributed equally to this work.

  2. Z Debyser and J Schwaller: Shared senior authorship.

Authors and Affiliations

  1. Department of Biomedicine, University Hospital and Children’s Hospital Base(UKBB) ZLF, Lab 318, Basel, Switzerland

    H Méreau, A Kutz, S Juge & J Schwaller

  2. Laboratory of Molecular Virology and Gene Therapy, Katholieke Universiteit, Leuven, Belgium

    J De Rijck, K Čermáková, J Demeulemeester, R Gijsbers, F Christ & Z Debyser

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  1. H Méreau
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Correspondence to Z Debyser or J Schwaller.

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HM, JDR, KC, JD, JS, ZD, FS and RG designed the research; HM, JDR, KC, AK, SJ and JS performed the research; HM, JS, JDR, KC and JD analyzed the data; and HM, JDR, JS, and ZD wrote the manuscript.

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Méreau, H., De Rijck, J., Čermáková, K. et al. Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75). Leukemia 27, 1245–1253 (2013). https://doi.org/10.1038/leu.2013.10

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