Article

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.

Download full-text

Full-text

Available from: Roderick Sorenson, Aug 06, 2015
2 Followers
 · 
292 Views
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: MLL aberrations are detected in around 5-10% of acute myeloid and lymphatic leukemias and an additional 5% of acute myeloid leukemias show a partial internal MLL duplication (PTD). MLL rearrangements are important for therapy stratification, assessment of minimal residual disease and for targeted therapies. However, no truly evidence-based RT-PCR methods for the detection of most of these aberrations have been published yet. Based on the large data collection of MLL genomic breakpoints in acute leukemias comprising more than 1.600 cases at the Diagnostic Center for Acute Leukemias (DCAL) in Frankfurt, Germany that provide an overview over the experimentally observed fusion transcript variants, we developed RT-PCR methods for the reliable detection of the 8 most common MLL aberrations (MLL-AF4, MLL-AF6, MLL-AF9, MLL-AF10, MLL-ENL, MLL-ELL, MLL-EPS15, MLL PTD), together accounting for around 90% of MLL-r cases. The easily implementable RT-PCRs should enable a reliable detection of these MLL fusion transcripts by RT-PCR. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Leukemia Research 11/2014; 39(2). DOI:10.1016/j.leukres.2014.11.017 · 2.69 Impact Factor
  • Source
    • "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 . "
    [Show abstract] [Hide abstract]
    ABSTRACT: The last three decades of cancer research were guided by the hypothesis that cancer cells evolve due to the accumulation of many genetic aberrations over time. While this is still true for most solid cancers, it might be different in haemato-malignant diseases, which are mostly characterized by chromosomal translocations that exhibit only few additional mutations. Some of the resulting fusion gene products functionally interfer with epigenetic mechanisms. Recent findings of mutated IDH1, IDH2, DNMT3A or TET2 in myelodysplastic syndrome/acute myeloid leukaemia patients underscore this notion, and point to the importance of epigenetic changes for developing tumour cells. This review aims (i) to give an overview about the different components of the epigenetic system, (ii) to describe the functions of different proteins or complexes that are involved in setting-up the epigenetic layer, (iii) to highlight some recent findings, and (iv) to describe the failures and successes when using drugs that are targeting epigenetic components.
    British Journal of Haematology 06/2012; 158(3):307-22. DOI:10.1111/j.1365-2141.2012.09193.x · 4.96 Impact Factor
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hippo pathway is an evolutionarily conserved signaling module that plays multiple roles in embryonic development. Components of the pathway, which includes a kinase cascade and a downstream complex composed of YAP and TEAD transcription factors, are dysregulated in a significant fraction of human cancers. In this issue of Genes & Development, Liu-Chittenden and colleagues (pp. 1300-1305) use genetic and pharmacological means to disrupt the active YAP-TEAD complex. As this intervention impedes tumorigenesis in the liver with no apparent effect on normal liver homeostasis, the work paves the way for the development of new strategies to target this pervasive oncogenic pathway.
    Genes & development 06/2012; 26(12):1263-7. DOI:10.1101/gad.196501.112 · 12.64 Impact Factor
Show more