LEDGF/p75 as a Target for Treatment of MLL-Dependent Lekemia and HIV Infection

K Čermáková1, P Tesina2,3, J Demeulemeester1, S El Ashkar1, H Méreau4, J Schwaller4, F Christ1, Z Debyser1, P Řezáčová2,3, V Veverka2 and J De Rijck1


1KU Leuven, Belgium; 2IOCB ASCR, Czech Republic; 3IMG ASCR, Czech Republic,  4UKBB ZLF, Switzerland


LEDGF/p75 is an epigenetic reader important for HIV integration and mixed lineage leukemia (MLL1) fusion-driven leukemia development and is considered an attractive therapeutic target for drug development [1]. The LEDGF/p75-MLL1-MENIN complex was structurally characterized, but only partially [2].

Using NMR spectroscopy, we identified and mapped an additional MLL-LEDGF/p75 interface. Colony forming assays in MLL-AF9+ leukemic cells expressing MLL interaction-defective LEDGF/p75 mutants revealed that this additional interface is essential for leukemic transformation. Interestingly, the newly defined interface overlaps with the binding site of known LEDGF/p75 interactor, the HIV integrase (HIV IN). Overexpression of a LEDGF/p75 binding peptide CP65, originally developed to inhibit the LEDGF/p75-HIV integrase interaction, impaired the clonogenic growth of primary murine MLL-AF9 expressing leukemic blasts. [1]

Since LEDGF/p75 contributes to HIV integration and leukemic transformation and has become a new therapeutic target for drug development, it is crucial to study its physiological interactions. In addition to HIV IN and MLL1-menin, the LEDGF/p75 integrase binding domain (IBD) also interacts with JPO2 and PogZ proteins [3,4].

Our recent data (manuscript in review) revealed structural details of LEDGF/p75 interactions with physiological binding partners, lead to identification of novel interaction partners and explained how HIV IN outcompetes these cellular proteins. The detailed mapping of interaction interfaces on the IBD revealed a notable overlap with the region involved in interaction with HIV integrase. This represents a challenge for selectivity of the recently developed IBD-interaction inhibitors.

1.         Cermakova, K., P. Tesina, et al., Validation and Structural Characterisation of the LEDGF/p75-MLL Interface as a New Target for the Treatment of MLL-Dependent Leukaemia. Cancer Res, 2014.

2.         Huang, J., B. Gurung, et al., The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature, 2012. 482(7386): p. 542-6.

3.         Bartholomeeusen, K., F. Christ, et al., Lens epithelium-derived growth factor/p75 interacts with the transposase-derived DDE domain of PogZ. J Biol Chem, 2009. 284(17): p. 11467-77.

4.         Bartholomeeusen, K., J. De Rijck, et al., Differential interaction of HIV-1 integrase and JPO2 with the C terminus of LEDGF/p75. J Mol Biol, 2007. 372(2): p. 407-21.