The PHD fingers of the human MLL and Drosophila trx proteins have strong amino acid sequence conservationbut their function is unknown. We have determined that these fingers mediate homodimerization andbinding of MLL to Cyp33, a nuclear cyclophilin. These two proteins interact in vitro and in vivo in mammaliancells and colocalize at specific nuclear subdomains. Overexpression of the Cyp33 protein in leukemia cellsresults in altered expression of HOX genes that are targets for regulation by MLL. These alterations aresuppressed by cyclosporine and are not observed in cell lines that express a mutant MLL protein without PHDfingers. These results suggest that binding of Cyp33 to MLL modulates its effects on the expression of target genes.