Clinical relevance of the PML/RAR-a gene rearrangement in acute promyelocytic leukaemia

The molecular mechanisms underlying the t(15;17) cytogenetic translocation of acute promyelocytic leukaemia (APL) have been recently elucidated. Together with new insights into the understanding of APL pathogenesis, such investigations also provided the availability of a novel leukemia-specific marker to be used for both diagnostic and monitoring studies. The chromosome breakpoints of the t(15;17) have been shown to involve the retinoic acid receptor alpha (RAR-a) gene and the newly described PML gene on chromosomes 17 and 15, respectively. Rearrangements of these loci are found in virtually 100% of APLs, including the microgranular variant subtype and cases displaying apparently normal karyotypes. In cases with ambiguous morphology, molecular diagnosis may therefore enable the prompt administration of APL-specific therapies, such as all-trans retinoic acid. Significantly, clinical response to this differentiating agent is predictable based on the presence of the specific PML/RAR-a rearrangement. Appropriate oligoprimers complementary to PML and RAR-a sequences nearby the DNA breakpoints may be successfully used in PCR experiments to amplify the PML/RAR-a hybrid gene and sensitively detect minimal residual disease. Preliminary PCR studies indicate that this approach might indeed prove a very important and reliable prognostic indicator in the follow up monitoring of APL patients. Early identification of impending relapse by PCR may suggest the use of additional treatment in patients at risk and significantly increase the probability of cure of the disease.