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Interaction of MLL Amino Terminal Sequences with Menin Is Required for Transformation

¹ Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan; ² Department of Pathology, University of Alabama, Birmingham, Alabama; ³ Laboratory of Biochemistry and Molecular Biology, The Rockefeller University, New York, New York; and ⁴ Department of Genetics, University of Erlangen, Erlangen, Germany

Requests for reprints: Jay L. Hess, Department of Pathology, University of Michigan Medical School, 5240 Medical Science I, 1301 Catherine Avenue, Ann Arbor, MI 48109-0602. Phone: 734-763-6384; Fax: 734-763-4782; E-mail: jayhess{at}med.umich.edu.

Rearrangements of the mixed lineage leukemia gene MLL are associated with aggressive lymphoid and myeloid leukemias. The resulting MLL fusion proteins enforce high-level expression of HOX genes and the HOX cofactor MEIS1, which is pivotal for leukemogenesis. Both wild-type MLL and MLL fusion proteins interact with the tumor suppressor menin and with the Hoxa9 locus in vivo. Here, we show that MLL sequences between amino acids 5 and 44 are required for interaction with menin and for the transformation of hematopoietic progenitors. Blocking the MLL-menin interaction by the expression of a dominant negative inhibitor composed of amino terminal MLL sequences down-regulates Meis1 expression and inhibits cell proliferation, suggesting that targeting this interaction may be an effective therapeutic strategy for leukemias with MLL rearrangements. [Cancer Res 2007;67(15):7275–83]

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