Molecular analysis of the t(15;17) translocation in acute promyelocytic leukaemia

APL (FAB M3) is a unique type of myeloid leukaemia characterized by specific clinical, morphological, cytogenetic and molecular features. An early and accurate diagnosis is necessary to initiate therapy and treat the life-threatening coagulopathy caused by release of procoagulants from the abundant promyelocytic granules. Cytogenetically the disease is characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17, t(15;17)(q21;q22), which is seen in almost every patient with APL but in no other form of malignancy. The presence of this translocation, often as the only karyotypic change, suggests that potentially leukaemogenic sequences are located at the breakpoints and are activated by rearrangement. The recent cloning of the breakpoints by three groups has demonstrated that the retinoic acid receptor alpha gene (RARA) on chromosome 17 is fused to a previously undescribed transcription factor gene, PML, on chromosome 15. The DNA-binding motifs of both the RARA and PML proteins, together with the ligand-binding domain of RARA, are combined in a single fusion protein which may dysregulate either retinoic acid or PML-sensitive pathways. Identification of these dysregulated target genes has become the next molecular goal for research on APL. Intriguingly, some APLs not only express the PML-RARA fusion protein but also the reciprocal RARA-PML fusion protein, although the contribution of this product is unclear. The PML-RARA chimaeric protein is presumably the target during the striking differentiation therapy achieved with all-trans retinoic acid. This therapy induces the malignant promyelocytes to mature and die, rather than continue proliferating. Moreover, it represents the first direct connection between a genetic defect and clinical treatment.(ABSTRACT TRUNCATED AT 250 WORDS)