We have previously shown that the t (15; 17) translocation specifically associated with acute promyelocytic leukemra (APL) fuses the retinoic acid receptor a (RARa) locus to an as yet unknown gene, initially called my/and now renamed PML. We report here that this gene product contains a novel zinc finger motif common to several DNA-binding proteins. The PML-RARa mRNA encodes a predicted 106 kd chimeric protein containing most of the PML sequences fused to a large part of RARa, including its DNA-and hormone-binding domains. In transient expression assays, the hybrid protein exhibits altered transectivating properties if compared with the wild-type RARa progenitor. Identical PML-RARa fusion points are found in several patients. These observations suggest that in APL, the t (l5; 17) translocation generates an RAR mutant that could contribute to leukemogenesis through interference with promyelocytic differentiation.