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

Jolanta Grembecka, Shihan He, Aibin Shi, Trupta Purohit, Andrew G. Muntean, Roderick J. Sorenson, Hollis D. Showalter, Marcelo J. Murai, Amalia M. Belcher, Thomas Hartley, Jay L. Hess, Tomasz Cierpicki

Research output: Contribution to journalArticle

204 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)277-284
Number of pages8
JournalNature chemical biology
Volume8
Issue number3
DOIs
StatePublished - Mar 2012
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Grembecka, J., He, S., Shi, A., Purohit, T., Muntean, A. G., Sorenson, R. J., Showalter, H. D., Murai, M. J., Belcher, A. M., Hartley, T., Hess, J. L., & Cierpicki, T. (2012). Menin-MLL inhibitors reverse oncogenic activity of MLL fusion proteins in leukemia. Nature chemical biology, 8(3), 277-284. https://doi.org/10.1038/nchembio.773