FUSION OF RETINOIC ACID RECEPTOR-ALPHA TO NUMA, THE NUCLEAR MITOTIC APPARATUS PROTEIN, BY A VARIANT TRANSLOCATION IN ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukaemia (APL) is uniquely associated with chromo somal translocations that disrupt the gene encoding the retinoic acid receptor, RARA. In more than 99% of cases, this disruption results in the formation of a PML-RARA gene fusion(1-4). Two rare variants of APL have been described, in which RARA is fused to one of two other genes , PLZF(5) and NPM6, Although RARA dysregulation is evidently important in APL, the role of the various fusion partners remains unclear. We h ave characterized a fourth APL gene fusion, which links exons encoding the retinoic acid and DNA-binding domains of RARA to 5' exons of NuMA , a gene that encodes the nuclear mitotic apparatus protein(7,8). The NuMA-RARA fusion protein exists in sheet-like nuclear aggregates with which normal NuMA partly co-localizes. In contrast to t(15;17) APL, th e intracellular distribution of PML is normal in these cells. Our resu lts suggest that interference with retinoid signalling, and not disrup tion of PML organization, is essential to the APL phenotype and implic ates for the first time an element of the mitotic apparatus in the mol ecular pathogenesis of human malignancy.