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

Nature Chemical Biology volume 8, pages 277–284 (2012)Cite this article

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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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Figure 1: Characterization of the menin-MLL inhibitors.
Figure 2: MI-2 induces growth arrest and inhibits transformation in MLL fusion-transformed bone marrow cells.
Figure 3: MI-2 induces hematopoietic differentiation and affects expression of MLL fusion protein target genes.
Figure 4: Effect of MI-2 and MI-3 in human MLL leukemia cells.

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Acknowledgements

This work was supported by grants from the Leukemia and Lymphoma Society (Translational Research Program grant 6070-09 to J.G. and Leukemia and Lymphoma Society Specialized Center of Research grant to J.L.H.), US National Institutes of Health R01 (1R01 CA-160467-01 to J.G.), Cancer Center (University of Virginia to J.G. and T.C.), Children's Leukemia Research Association (to J.G.), American Cancer Society (RSG-11-082-01-DMC to T.C.) and startup funds to J.G. and T.C. provided by the Department of Pathology (University of Michigan). The authors greatly appreciate support from J. Bushweller (University of Virginia) for providing the research environment for carrying out part of these studies. We are grateful to M. Larsen from the Center for Chemical Genomics, University of Michigan, for technical expertise during HTS. We would like to thank J. Tan (University of Michigan) for discussion of experimental procedures and R. Craig from the Department of Pathology (University of Michigan) for technical support with flow cytometry experiments.

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Authors and Affiliations

  1. Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA

    Jolanta Grembecka, Shihan He, Aibin Shi, Trupta Purohit, Andrew G Muntean, Marcelo J Murai, Thomas Hartley, Jay L Hess & Tomasz Cierpicki

  2. Department of Medicinal Chemistry, University of Michigan, Ann Arbor, Michigan, USA

    Roderick J Sorenson & Hollis D Showalter

  3. University of Virginia, Charlottesville, Virginia, USA

    Amalia M Belcher

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  1. Jolanta Grembecka
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Contributions

J.G. and T.C. initiated the project, led the project team, designed experiments and analyzed results. S.H., T.P. and A.G.M. performed cellular assays. A.S., R.J.S. and H.D.S. synthesized compounds. M.J.M. and T.H. expressed and purified proteins and ran ITC and thermal shift assays. A.M.B. performed biochemical assays. J.L.H. designed experiments and analyzed results. J.G. and T.C. wrote the paper with input from all authors.

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Correspondence to Jolanta Grembecka or Tomasz Cierpicki.

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The authors declare no competing financial interests.

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Grembecka, J., He, S., Shi, A. et al. Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nat Chem Biol 8, 277–284 (2012). https://doi.org/10.1038/nchembio.773

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