Menin critically links MLL proteins with LEDGF 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 MLL (mixed-lineage leukemia) histone methyltransferase with LEDGF (lens epithelium-derived growth factor), a chromatin-associated protein previously implicated in leukemia, autoimmunity, and HIV-1 pathogenesis. LEDGF 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 LEDGF while preserving MLL interaction but nevertheless compromise 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.
Yokoyama
Akihiko
A
Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA. ayokoyam@ncc.go.jp
Cleary
Michael L
ML
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly; D015973:Gene Expression Regulation, Leukemic; D006367:HeLa Cells; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018761:Multiple Endocrine Neoplasia Type 1 / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000201:enzymology / Q000378:metabolism*; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011496:Protein Methyltransferases; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D020298:U937 Cells
D048868:Adaptor Proteins, Signal Transducing; D002843:Chromatin; D018398:Homeodomain Proteins; C497422:KMT2A protein, human; C105373:MEN1 protein, human; C504649:PSIP1 protein, human; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C097899:homeobox protein HOXA9; D051788:Myeloid-Lymphoid Leukemia Protein; D000076983:Histone Methyltransferases; D011496:Protein Methyltransferases; D011495:Histone-Lysine N-Methyltransferase