title: Impairing MLL-fusion gene-mediated transformation by dissecting critical interactions with the lens epithelium-derived growth factor (LEDGF/p75).
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-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.
authors: Department of Biomedicine, University Hospital and Children's Hospital Base(UKBB) ZLF, Lab 318, Basel, Switzerland.
authors: H
authors: H
authors: Méreau
authors: J
authors: J
authors: De Rijck
authors: K
authors: K
authors: Cermáková
authors: A
authors: A
authors: Kutz
authors: S
authors: S
authors: Juge
authors: J
authors: J
authors: Demeulemeester
authors: R
authors: R
authors: Gijsbers
authors: F
authors: F
authors: Christ
authors: Z
authors: Z
authors: Debyser
authors: J
authors: J
authors: Schwaller
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000235:genetics; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics* / Q000378:metabolism; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D011993:Recombinant Fusion Proteins; C119380:lens epithelium-derived growth factor; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; C497423:Kmt2a protein, mouse