AbstractThe translocation t(15;17) associated with acute promyelocytic leukemia (APL) results in fusion of the retinoic acid receptor alpha (RARA) gene on chromosome 17 with the putative transcription factor gene,PML, on chromosome 15. We report three cases of APL with complex cytogenetic translocations and five cases with atypical phenotypic features with rearrangements within or adjacent to the second intron of theRARAgene. Two patients demonstrated three‐way translocations involving chromosomes 3, 15, and 17, but with differing breakpoints on the short arm of chromosome 3. A third patient developed a complex karyotype at the time of third relapse, but with no change inRARAandPMLgene rearrangement pattern. Three patients had normal karyotypes; however, only small numbers of cells could be analyzed. One patient's leukemic cells expressed the T‐cell‐associated antigen CD2 and revealed T‐cell receptor β and γ gene rearrangements. The localization of breakpoints to the second intron of theRARAgene in cytogenetically and phenotypically atypical cases provides additional support for a requisite role of thePML/RARAfusion gene in the pathogenesis of APL.Genes Chrom Cancer 9:49‐56 (1994).© 1994 Wil