Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia

• Published in: Nature chemical biology Vol. 8; no. 3; pp. 277 - 284
• Main Authors: Grembecka, Jolanta, He, Shihan, Shi, Aibin, Purohit, Trupta, Muntean, Andrew G, Sorenson, Roderick J, Showalter, Hollis D, Murai, Marcelo J, Belcher, Amalia M, Hartley, Thomas, Hess, Jay L, Cierpicki, Tomasz
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 29.01.2012; Nature Publishing Group
• Subjects: 631/92/556; 631/92/613; 631/92/96; 692/699/67/1990/283; Animals; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Apoptosis; Apoptosis - drug effects; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; Cell Biology; Cell Differentiation - drug effects; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Chemistry; Chemistry and Materials Science; Chemistry/Food Science; Cofactors; Differentiation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Fusion protein; Gene expression; HEK293 Cells; Histone-Lysine N-Methyltransferase; Humans; Inhibitors; Leukemia; Leukemia - drug therapy; Leukemia - genetics; Leukemia - metabolism; Leukemia - pathology; Leukemogenesis; MEN1 protein; Mice; MLL protein; Molecular biology; multiple endocrine neoplasia; Mutation; Myeloid-Lymphoid Leukemia Protein - antagonists & inhibitors; Myeloid-Lymphoid Leukemia Protein - genetics; Myeloid-Lymphoid Leukemia Protein - metabolism; Oncology; Prognosis; Proteins; Proto-Oncogene Proteins - antagonists & inhibitors; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Structure-Activity Relationship; Transformation; Translocation
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.773

MLL fusion genes often encode leukemogenic proteins that depend on interaction with menin, a component of the MLL SET1-like histone methyltransferase complex. MI-2 and MI-3 are the first small molecules that can block menin–MLL fusion protein interaction and their oncogenic effects in cells. 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.