The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV

Marcelo J. Murai, Jonathan Pollock, Shihan He, Hongzhi Miao, Trupta Purohit, Adam Yokom, Jay Hess, Andrew G. Muntean, Jolanta Grembecka, Tomasz Cierpicki

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Lens epithelium-derived growth factor (LEDGF) is a chromatin-associated protein implicated in leukemia and HIV type 1 infection. LEDGF associates with mixed-lineage leukemia (MLL) fusion proteins andmenin and is required for leukemic transformation. To better understand themolecular mechanismunderlying the LEDGF integrase-binding domain (IBD) interaction with MLL fusion proteins in leukemia, we determined the solution structure of the MLL-IBD complex. We found a novel MLLmotif, integrase domain bindingmotif 2 (IBM2), which binds to a well-defined site on IBD. Point mutations within IBM2 abolished leukemogenic transformation by MLL-AF9, validating that this newly identified motif is essential for the oncogenic activityofMLLfusionproteins. Interestingly, the IBM2bindingsiteon IBDoverlaps with the binding site for the HIV integrase (IN), and IN was capable of efficiently sequestering IBD fromthemenin-MLL complex.Ashort IBM2 peptidebinds to IBDdirectly andinhibitsboth the IBD-MLL/menin and IBD-IN interactions. Our findings show that the same site on IBD is involved in binding to MLL and HIV-IN, revealing an attractive approach to simultaneously target LEDGF in leukemia and HIV.

Original languageEnglish (US)
Pages (from-to)3730-3737
Number of pages8
JournalBlood
Volume124
Issue number25
DOIs
StatePublished - Dec 11 2014
Externally publishedYes

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Integrases
Leukemia
HIV
Myeloid-Lymphoid Leukemia Protein
Therapeutics
HIV Integrase
lens epithelium-derived growth factor
Fusion reactions
Proteins
Point Mutation
Chromatin
HIV Infections
HIV-1

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. / Murai, Marcelo J.; Pollock, Jonathan; He, Shihan; Miao, Hongzhi; Purohit, Trupta; Yokom, Adam; Hess, Jay; Muntean, Andrew G.; Grembecka, Jolanta; Cierpicki, Tomasz.

In: Blood, Vol. 124, No. 25, 11.12.2014, p. 3730-3737.

Research output: Contribution to journalArticle

Murai, MJ, Pollock, J, He, S, Miao, H, Purohit, T, Yokom, A, Hess, J, Muntean, AG, Grembecka, J & Cierpicki, T 2014, 'The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV', Blood, vol. 124, no. 25, pp. 3730-3737. https://doi.org/10.1182/blood-2014-01-550079
Murai, Marcelo J. ; Pollock, Jonathan ; He, Shihan ; Miao, Hongzhi ; Purohit, Trupta ; Yokom, Adam ; Hess, Jay ; Muntean, Andrew G. ; Grembecka, Jolanta ; Cierpicki, Tomasz. / The same site on the integrase-binding domain of lens epithelium-derived growth factor is a therapeutic target for MLL leukemia and HIV. In: Blood. 2014 ; Vol. 124, No. 25. pp. 3730-3737.
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