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Molecular and Cellular Biology, July 2004, p. 5639-5649, Vol. 24, No. 13
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.13.5639-5649.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Leukemia Proto-Oncoprotein MLL Forms a SET1-Like Histone Methyltransferase Complex with Menin To Regulate Hox Gene Expression

Akihiko Yokoyama,1 Zhong Wang,1 Joanna Wysocka,2,{dagger} Mrinmoy Sanyal,1 Deborah J. Aufiero,2 Issay Kitabayashi,3 Winship Herr,2 and Michael L. Cleary1*

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305,1 Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724,2 Molecular Oncology Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan3

Received 16 February 2004/ Returned for modification 7 March 2004/ Accepted 19 April 2004

MLL (for mixed-lineage leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Its product, a homolog of Drosophila melanogaster trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. Here we report the biochemical purification of MLL and demonstrate that it associates with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including a homolog of Ash2, another Trx-G group protein. Two other members of the novel MLL complex identified here are host cell factor 1 (HCF-1), a transcriptional coregulator, and the related HCF-2, both of which specifically interact with a conserved binding motif in the MLLN (p300) subunit of MLL and provide a potential mechanism for regulating its antagonistic transcriptional properties. Menin, a product of the MEN1 tumor suppressor gene, is also a component of the 1-MDa MLL complex. Abrogation of menin expression phenocopies loss of MLL and reveals a critical role for menin in the maintenance of Hox gene expression. Oncogenic mutant forms of MLL retain an ability to interact with menin but not other identified complex components. These studies link the menin tumor suppressor protein with the MLL histone methyltransferase machinery, with implications for Hox gene expression in development and leukemia pathogenesis.

* Corresponding author. Mailing address: Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305. Phone: (650) 723-5471. Fax: (650) 498-6222. E-mail: mcleary{at}stanford.edu.

{dagger} Present address: Laboratory of Chromatin Biology, The Rockefeller University, New York, New York 10021.

Molecular and Cellular Biology, July 2004, p. 5639-5649, Vol. 24, No. 13
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.13.5639-5649.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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