In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 18 ( 2014-09-15), p. 5139-5151
Abstract:
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.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/0008-5472.CAN-13-3602
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2014
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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