Transcriptional Deregulation by MLL Fusion Proteins

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DESCRIPTION (provided by applicant): Rearrangements of the mixed lineage leukemia gene (MLL) are associated with aggressive lymphoid and myeloid leukemias in both children and adults. MLL, which is homologous to Drosophila Trithorax, is one of a growing family of epigenetic regulators of transcription including CBP, MOZ, and IN11 implicated in human malignancies. Fusion of MLL to one of more than 25 different translocation partners, which in general share little sequence homology, converts it into a leukemogenic oncoprotein. The mechanism of transformation by MLL fusion proteins is poorly understood although it undoubtedly involves transcriptional deregulation of target genes. Efforts to study this function has been hampered by the lack of knowledge of target genes that has both precluded studies of alterations in signal transduction pathways, as well as functional studies to discern mechanisms of activation at target promoters. We have now identified a c-MYC-dependent promoter that is strongly transactivated by 5 different MLL fusion proteins as well as by dimerized or exon-duplicated forms of MLL resembling those occurring in human leukemias. Our data indicate that domains of MLL and translocation partners required for transactivation are also required for transformation, and also that transactivation is dependent on the ATPase-dependent SWI/SNF chromatin remodeling complex. Our overall goal is to better define how MLL fusion proteins deregulate expression of target genes. To this end 1) The role of dimerization and oligomerization of MLL in transactivation and transformation will be defined, and the effect of mutagenesis of four conserved domains of MLL on these functions will be assessed. 2) Direct targets of MLL fusion proteins will be identified. 3) We will determine if MLL induced leukemia is reversible. 4) The role of the SWI/SNF complex in MLL fusion protein transactivation and transformation will be explored.