The primary cytogenetic abnormality in acute promyelocytic leukemia (APL; FAB M3) is a reciprocal translocation, t( 15; I7)(q22;q I2), which serves t o fuse the PML gene on chromosome I5 t o the retinoic acid receptor alpha (RAM) gene on chromosome 17. A PML-MM fusion message transcribed from the der( 15) is thought t o mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3; I5)(q2 I ;q22) and t(X I5)(p I I ;q22), have previously been reported who lack cytogenetic involvement of chromosome 17, although their breakpoint positions on chromosome I5 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybridization of these two patients, in which we wanted t o determine whether the PML gene has alternative fusion partners or whether cryptic rearrangement of the R A M locus has occurred instead. A cryptic involvement of M R A was demonstrated in both patients by a combination of Southern analysis, reverse transcription coupled t o PCR (RT-PCR), and fluorescence in situ hybridization. The results indicate an absolute requirement for the rearrangement of the R A M gene in the pathogenesis of APL and underline the importance of R A M during normal myeloid differentiation. Genes Chrom Cancer 9: 234-243 (1994).