Document Detail


Impairing MLL-fusion gene mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75).
MedLine Citation:
PMID:  23318960     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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.
Authors:
H Méreau; J De Rijck; K Cermáková; A Kutz; S Juge; J Demeulemeester; R Gijsbers; F Christ; Z Debyser; J Schwaller
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-15
Journal Detail:
Title:  Leukemia : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K     Volume:  -     ISSN:  1476-5551     ISO Abbreviation:  Leukemia     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-15     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8704895     Medline TA:  Leukemia     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
Department of Biomedicine, University Hospital & Children's Hospital (UKBB), KU Leuven, Belgium.
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