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. Iden

SUBMITTER: Grembecka J 

PROVIDER: S-EPMC3401603 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature