Title: Impairing MLL-fusion gene mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75)
Authors: Méreau, H *
De Rijck, Jan *
Cermakova, Katerina
Kutz, A
Juge, S
Demeulemeester, Jonas
Gijsbers, Rik
Christ, Frauke
Debyser, Zeger
Schwaller, J # ×
Issue Date: Jun-2013
Publisher: Nature Publishing Group
Series Title: Leukemia vol:27 issue:6 pages:1245-1253
Article number: 10.1038/leu.2013.10
Abstract: The lens epithelium-derived growth factor (LEDGF/p75) tethers the mixed lineage leukemia (MLL1) protein complex to chromatin. Likewise, LEDGF/p75 tethers the human immunodeficiency virus 1 (HIV-1) pre-integration complex to chromatin. We previously demonstrated that expression of the C-terminal fragment fused to eGFP (eGFP-LEDGF(325-530)) 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 LEDGF(325-530) 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 LEDGF(325-530) 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, LEDGF(424-435) and LEDGF(375-386) phenocopying these effects. Both LEDGF(325-530) and the smaller active peptides were able to disrupt the LEDGF/p75-MLL interaction. Expression of LEDGF(325-530) or LEDGF(375-386) 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.Leukemia accepted article preview online, 15 January 2013; doi:10.1038/leu.2013.10.
ISSN: 0887-6924
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Virology and Gene Therapy
* (joint) first author
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Méreau et al. (2013).pdf Accepted 1502KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science