MOLECULAR ANALYSIS OF SIMPLE VARIANT TRANSLOCATIONS IN ACUTE PROMYELOCYTIC LEUKEMIA

The primary cytogenetic abnormality in acute promyelocytic leukemia (A PL; FAB M3) is a reciprocal translocation, t(15;17)(q22;q12), which se rves to fuse the PML gene on chromosome 15 to the retinoic acid recept or alpha (RARA) gene on chromosome 17. A PML-RARA fusion message trans cribed from the der(15) is thought to mediate leukemogenesis. Two APL patients with simple variants of this translocation, t(3;15)(q21;q22) and t(X;15)(p11;q22), have previously been reported who lack cytogenet ic involvement of chromosome 17, although their breakpoint positions o n chromosome 15 still suggest the involvement of the PML gene. Here we report on a combined analysis by molecular genetics and in situ hybri dization of these two patients, in which we wanted to determine whethe r the PML gene has alternative fusion partners or whether cryptic rear rangement of the RARA locus has occurred instead. A cryptic involvemen t of RARA was demonstrated in both patients by a combination of Southe rn analysis, reverse transcription coupled to PCR (RT-PCR), and fluore scence in situ hybridization. The results indicate an absolute require ment for the rearrangement of the RARA gene in the pathogenesis of APL and underline the importance of RARA during normal myeloid differenti ation. (C) 1994 Wiley-Liss, Inc.