Validation and structural characterization of the LEDGF/p75-MLL interface as a new target for the treatment of MLL-dependent leukemia
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
25082813
DOI
10.1158/0008-5472.can-13-3602
PII: 0008-5472.CAN-13-3602
Knihovny.cz E-resources
- MeSH
- Leukemia, Myeloid, Acute genetics metabolism MeSH
- Molecular Targeted Therapy MeSH
- Oncogene Proteins, Fusion genetics metabolism MeSH
- Histone-Lysine N-Methyltransferase chemistry genetics metabolism MeSH
- HIV Integrase chemistry metabolism MeSH
- Humans MeSH
- Magnetic Resonance Spectroscopy MeSH
- Intercellular Signaling Peptides and Proteins chemistry genetics metabolism MeSH
- MCF-7 Cells MeSH
- Models, Molecular MeSH
- Mice MeSH
- Myeloid-Lymphoid Leukemia Protein chemistry genetics metabolism MeSH
- Protein Binding MeSH
- Binding Sites MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Oncogene Proteins, Fusion MeSH
- Histone-Lysine N-Methyltransferase MeSH
- HIV Integrase MeSH
- KMT2A protein, human MeSH Browser
- Kmt2a protein, mouse MeSH Browser
- lens epithelium-derived growth factor MeSH Browser
- Intercellular Signaling Peptides and Proteins MeSH
- Myeloid-Lymphoid Leukemia Protein MeSH
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. Cancer Res; 74(18); 5139-51. ©2014 AACR.
References provided by Crossref.org
The Impact of Lens Epithelium-Derived Growth Factor p75 Dimerization on Its Tethering Function
A ubiquitous disordered protein interaction module orchestrates transcription elongation
Affinity switching of the LEDGF/p75 IBD interactome is governed by kinase-dependent phosphorylation
Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif
