Menin critically links MLL proteins with LEDGE on cancer-associated target genes

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 MILL (mixed-lineage leukemia) histone methyltransferase with LEDGE (lens epithelium-derived growth factor), a chromatin-associated protein previously implicated in leukemia, autoimmunity, and HIV-1 pathogenesis. LEDGE is required for both MLL-dependent transcription and leukemic transformation. Conversely, a subset of menin mutations in multiple endocrine neoplasia type 1 patients abrogate interaction with LEDGE while preserving MLL interaction but nevertheless compromise MLL/menin-dependent functions. Thus, LEDGE critically associates with MLL and menin at the nexus of transcriptional pathways that are recurrently targeted in diverse diseases.