Menin Critically Links MLL Proteins with LEDGF on Cancer-Associated Target Genes

Abstract

Summary Menin displays the unique ability to either promote oncogenic function in the hematopoietic lineage or suppress tumorigenesis in the endocrine lineage, however its molecular mechanism of action has not been defined. We demonstrate here that these discordant functions are unified by menin's ability to serve as a molecular adaptor that physically links the MLL histone methyltransferase with LEDGF, a chromatin-associated protein previously implicated in leukemia, auto-immunity and HIV-1 pathogenesis. LEDGF is required for both MLL-dependent transcription and leukemic transformation. Conversely, a subset of menin mutations in MEN1 patients abrogates interaction with LEDGF while preserving MLL interaction, but nevertheless compromises MLL/menin-dependent functions. Thus, LEDGF critically associates with MLL and menin at the nexus of transcriptional pathways that are recurrently targeted in diverse diseases.

Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif

“…Sequence alignment of the IBD-interacting regions of JPO2, PogZ and MLL1 revealed a consensus IBM ((E/D)-X-E-X-F-X-G-F), which was validated through comprehensive mutational analysis. IBMs were also identified in two other established LEDGF/p75 binding partners (MLL2 and CDC7-ASK) 32,52 . The consensus motif harbours two phenylalanine residues; the second phenylalanine is preceded by a glycine, most likely to avoid steric hindrance.…”

“…Along with the PWWP domain, the IBD has a key role in the known physiological and pathological functions of LEDGF/p75 by mediating its interactions with various cellular and viral proteins [30][31][32]52 . Before this work, the interactions of a diverse set of proteins with the IBD were not fully understood, despite their importance to the development of therapies targeting LEDGF/p75 interactions to block MLL fusionmediated leukaemic transformation and HIV integration 53,54 .…”

The heterogeneity of pediatric MLL-rearranged acute myeloid leukemia

“…27 The MLL N fragment has a binding site for MEN1 at the N-terminal end and both recruit PSIP1(LEDGF). 28 PSIP1 then contacts the chromatin by a PWWP domain. MLL N also contains a CxxC domain, which specifically binds to unmethylated DNA.…”

“…Indeed, excision of Men1 potently inhibits the proliferation of MLL-MLLT3-transformed cells and Hoxa9 expression in mice, 124 and similarly, knockdown of Psip1 impaired Hoxa9 expression. 28 This raises the possibility to block the function of Men1 or PSIP1 as a new targeted therapy in MLL rearrangements. The MLL protein also contains a CxxC domain, which is conserved in all MLL-fusion proteins and specifically binds to unmethylated CpG dinucleotides.…”

Regulation of vitamin D receptor function in MEN1-related parathyroid adenomas

“…Menin is part of the MLL1 and MLL2, but not of the MLL3 or MLL4 complexes (Lee et al, 2006). The menin-MLL1 histone methyltransferase (HMT) complex was found to be important for -catenin regulated transcription of the c-Myc gene and is stabilised by the chromatin-associated protein lens epithelium-derived growth factor (LEDGF) (Sierra et al, 2006, Yokoyama andCleary, 2008). The menin-MLL1 complex can also activate the expression of several other genes involved in cell proliferation such as the CDKN2C and CDKN1B cyclin-dependent kinase inhibitor genes and genes involved in cell differentiation such as several homeoboxdomain (Hox) genes (Hughes et al, 2004, Yokoyama et al, 2004, Milne et al, 2005.…”