MLL (Mixed Lineage Leukemia) is a proto-oncogene that is mutated in a variety of human leukemias. Oncogenic MLL fusion genes created by chromosomal translocations cause acute myeloid or lymphoid leukemias often in infants. MLL, a homolog of Drosophila trithorax, displays intrinsic histone methyltransferase activity and functions genetically to maintain embryonic Hox gene expression. But its regulatory mechanism is poorly understood. Our previous studies showed that MLL undergoes a variety of post-translational modifications to assume its mature form. Most uniquely, MLL is proteolytically processed after translation into two major polypeptides, MLL-N and MLL-C, which possess opposite transcriptional properties and associate with each other through their intra-molecular interaction domains. In order to understand the function of MLL and its regulatory mechanism, we performed the biochemical purification of MLL. MLL-C was found to associate with a cohort of proteins shared with the yeast and human SET1 histone methyltransferase complexes, including ASH2L (highly conserved protein of unknown function whose Drosophila homolog genetically interacts with trithorax), WDR5 and RBBP5 (two WD repeat proteins implicated in histone binding) to form an MLL-C histone methyltransferase (HMT) sub-complex centered on its SET domain. 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 MLL-N (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.

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