Variant and masked translocations in acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is characterized by a unique hemorrhagic syndrome, disseminated intravascular coagulation, and the association with the specific (15;17 chi q22-23:q12-21) translocation, which disrupts the retinoic acid receptor alpha (RARA) and the promyelocytic leukemia (PML) genes. The t(15;17) leads to the formation of two reciprocal fusion genes, PML/RARA on chromosome 15 and RARA/PML on chromosome 17; it is responsible for the unique response of the disease to retinoic acid (ATRA) treatment. As was described for chronic myeloid leukemia and its associated t(9;22) [Philadelphia chromosome], variant translocations have been reported in APL, which are either complex translocations involving additional chromosome(s), or simple variant translocations involving only either one chromosome 15 or 17 and any of several chromosomes. Rearrangements of RARA and PML were documented in some of these variant translocations. In contrast, recent molecular analysis of APL cases with cytogenetically normal chromosomes 15 and 17 revealed the occurrence of submicroscopic translocations, leading to the formation of non reciprocal fusion genes, either PML/RARA or RARA/PML only. Detailed analysis of such cases may shed light on the mechanisms of translocation, on the selection of oncogenic products, and on the respective role(s) of the products of the translocation. Demonstration of the existence, in some APL-like leukemias, of masked translocations with involvement of PML and RARA, thus allows to (i) confirm the diagnosis of APL, (ii) adapt the treatment and (iii) monitor the residual disease. Finally APL-like leukemias were recently reported, with either a t(11;17) or t(5;17), resulting in the fusion of RARA to genes other than PML; these patients do not appear to respond to ATRA treatment. Altogether, these results emphasize the usefulness of a molecular definition of APL.