title: Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia.
abstract: Translocations involving the mixed lineage leukemia (MLL) gene result in human acute leukemias with very poor prognosis. The leukemogenic activity of MLL fusion proteins is critically dependent on their direct interaction with menin, a product of the multiple endocrine neoplasia (MEN1) gene. Here we present what are to our knowledge the first small-molecule inhibitors of the menin-MLL fusion protein interaction that specifically bind menin with nanomolar affinities. These compounds effectively reverse MLL fusion protein-mediated leukemic transformation by downregulating the expression of target genes required for MLL fusion protein oncogenic activity. They also selectively block proliferation and induce both apoptosis and differentiation of leukemia cells harboring MLL translocations. Identification of these compounds provides a new tool for better understanding MLL-mediated leukemogenesis and represents a new approach for studying the role of menin as an oncogenic cofactor of MLL fusion proteins. Our findings also highlight a new therapeutic strategy for aggressive leukemias with MLL rearrangements.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA. jolantag@umich.edu
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Shihan
authors.initials: S
authors.lastname: He
authors.forename: Aibin
authors.initials: A
authors.lastname: Shi
authors.forename: Trupta
authors.initials: T
authors.lastname: Purohit
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Muntean
authors.forename: Roderick J
authors.initials: RJ
authors.lastname: Sorenson
authors.forename: Hollis D
authors.initials: HD
authors.lastname: Showalter
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Murai
authors.forename: Amalia M
authors.initials: AM
authors.lastname: Belcher
authors.forename: Thomas
authors.initials: T
authors.lastname: Hartley
authors.forename: Jay L
authors.initials: JL
authors.lastname: Hess
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D057809:HEK293 Cells; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D051788:Myeloid-Lymphoid Leukemia Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; C497422:KMT2A protein, human; C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase