Abstract 3225: LEDGF IBD domain represents therapeutic target for MLL leukemia and HIV

Abstract

Abstract Lens epithelium-derived growth factor (LEDGF) is a chromatin associated protein implicated in cell survival, cancer, autoimmune diseases and HIV pathogenesis. LEDGF is also involved in recurring chromosomal translocations with nucleoporin NUP98 in acute leukemia, and the LEDGF/p75 isoform is consistently upregulated in a subset of acute myeloid leukemias (AML) resistant to chemotherapy. Moreover, it has been established that LEDGF is an essential co-factor required for oncogenic activity of MLL fusion proteins in leukemia. LEDGF interacts simultaneously with MLL and menin and is necessary for up-regulation of HOXA9 gene and for leukemogenic transformation by MLL fusion proteins in vivo. Therefore, LEDGF represent a valuable molecular target for therapeutic intervention as a novel targeted therapy for MLL leukemia patients. Furthermore, targeting LEDGF may represent an attractive alternative to inhibition of the menin-MLL interaction as it will allow preserving the function of menin, a known tumor suppressor in endocrine tissues. We determined the solution structure of MLL fragment bound to LEDGF IBD domain and identified a novel hydrophobic motif within MLL, which we called IBM2, that is required for high affinity interaction with LEDGF. Point mutations within IBM2 abolished leukemogenic activity of MLL-AF9, indicating that IBM2 represents a critical site for formation of a high affinity menin-MLL-LEDGF complex. Furthermore, we found that short peptide corresponding to IBM2 binds to IBD domain and disrupts the interaction of LEDGF with the menin-MLL complex, providing a proof of concept that the novel interface on IBD domain we identified represents a druggable site for small molecule intervention. LEDGF plays also an essential role in pathogenesis of HIV-1 virus and is required for integration of viral cDNA. Targeting HIV integrase to disrupt the interaction with LEDGF has been recognized as an attractive approach to develop new anti-viral agents. Importantly, the new MLL binding site on IBD domain we found overlaps with the binding site of HIV integrase. Therefore, targeting the IBM2 site on IBD may represent a novel approach to target the LEDGF-integrase interaction. In summary, our findings pave the way towards development of new therapeutic agents with dual applications for both MLL leukemias and HIV. Citation Format: Tomasz Cierpicki, Marcelo J. Murai, Jonathan Pollock, Trupta Purohit, Shihan He, Adam Yokom, Jay L. Hess, Andrew G. Muntean, Jolanta Grembecka. LEDGF IBD domain represents therapeutic target for MLL leukemia and HIV. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3225. doi:10.1158/1538-7445.AM2014-3225