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

Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA.
Nature Chemical Biology (Impact Factor: 13.22). 01/2012; 8(3):277-84. DOI: 10.1038/nchembio.773
Source: PubMed

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.

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Available from: Roderick Sorenson, Aug 06, 2015
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    • "In most cases – with a few, but notable exceptions [1] – these patients show an unfavorable clinical course and stem cell transplantation is often recommended, at least in adult cases. Since acute leukemia patients with MLL aberrations exhibit a distinct gene expression profile [2], they are candidates for targeted therapies [3] [4] [5] [6]. MLL aberrations have also been shown to be useful molecular markers for the detection of minimal residual disease (MRD). "
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    • "They developed two specific molecules (MI-2 and MI-3; IC 50 c. 450 and 650 nmol/l, respectively) that competitively blocked the interaction between MENIN1 and the N-terminus of MLL (Grembecka et al, 2012). Disruption of this important interaction has been shown to cause growth arrest and necrosis/apoptosis in cell culture experiments (KOPN-8; MV4;11; THP-1), strong impairment of colony formation, induced haematopoietic differentiation of MLL-MLLT3/MLLT1 expressing bone marrow cells and down-regulation of typical HOXA gene signatures . "
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    • "because it is one of a limited number of studies indicating the viability of pharmacological approaches that target transcriptionally active complexes. For example, small molecules have been described that inhibit the formation of a complex between the Menin adaptor protein and fusion proteins containing the MLL histone methyltransferase , reversing the oncogenic activity of that complex (Grembecka et al. 2012). Similarly, small molecules that inhibit the ability of the bromodomain-containing protein Brd4 to bind to acetylated histones have broad activity against a number of leukemia cell lines (Zuber et al. 2011). "
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