Validation and Structural Characterization of the LEDGF/p75-MLL Interface as a New Target for the Treatment of MLL-Dependent Leukemia

0433970 - ÚOCHB 2015 RIV US eng J - Journal Article
Čermáková, K. - Těšina, Petr - Demeulemeester, J. - El Ashkar, S. - Méreau, H. - Schwaller, J. - Řezáčová, Pavlína - Veverka, Václav - De Rijck, J.
Validation and Structural Characterization of the LEDGF/p75-MLL Interface as a New Target for the Treatment of MLL-Dependent Leukemia.
Cancer Research. Roč. 74, č. 18 (2014), s. 5139-5151. ISSN 0008-5472. E-ISSN 1538-7445
R&D Projects: GA MŠMT(CZ) LK11205; GA MŠMT(CZ) 7E08066; GA MŠMT LO1302
Institutional support: RVO:61388963
Keywords : MLL * leukemia * LEDGF/p75
Subject RIV: CE - Biochemistry
Impact factor: 9.329, year: 2014

Mixed lineage leukemia (MLL) fusion-driven acute leukemias represent a genetically distinct subset of leukemias with poor prognosis. MLL forms a ternary complex with the lens epithelium-derived growth factor (LEDGF/p75) and MENIN. LEDGF/p75, a chromatin reader recognizing H3K36me3 marks, contributes to the association of the MLL multiprotein complex to chromatin. Formation of this complex is critical for the development of MLL leukemia. Available X-ray data represent only a partial structure of the LEDGF/p75-MLL-MENIN complex. Using nuclear magnetic resonance spectroscopy, we identified an additional LEDGF/p75-MLL interface, which overlaps with the binding site of known LEDGF/p75 interactors-HIV-1 integrase, PogZ, and JPO2. Binding of these proteins or MLL to LEDGF/p75 is mutually exclusive. The resolved structure, as well as mutational analysis, shows that the interaction is primarily sustained via two aromatic residues of MLL (F148 and F151). Colony-forming assays in MLL-AF9(+) leukemic cells expressing MLL interaction-defective LEDGF/p75 mutants revealed that this interaction is essential for transformation. Finally, we show that the clonogenic growth of primary murine MLL-AF9-expressing leukemic blasts is selectively impaired upon overexpression of a LEDGF/p75-binding cyclic peptide CP65, originally developed to inhibit the LEDGF/p75-HIV-1 integrase interaction. The newly defined protein-protein interface therefore represents a new target for the development of therapeutics against LEDGF/p75-dependent MLL fusion-driven leukemic disorders.
Permanent Link: http://hdl.handle.net/11104/0238385