THE MOLECULAR-GENETICS OF ACUTE PROMYELOCYTIC LEUKEMIA

The chromosome breakpoints of the acute promyelocytic leukemia(APL)-sp ecific 15;17 translocation have recently been isolated. They are local ized on a previously unknown gene, PML, on chromosome 15 and in the ge ne that encodes the alpha retinoic acid receptor (RARalpha) on 17. The translocation, which is balanced and reciprocal, leads to the formati on of two fusion genes, PML/RARalpha and RARalpha/PML. Both are expres sed in APL. The PML/RARalpha gene codes for two abnormal proteins: the PML/RARalpha fusion protein and an abnormal PML protein, the RARalpha /PML gene encodes the RARalpha/PML fusion protein. Experiments to inve stigate the biological activity of the abnormal translocation products are in progress. Preliminary results suggest that the PML/RARalpha fu sion protein is responsible for two important properties of the APL ph enotype: the differentiation block characteristic of the leukemic blas ts and the high sensitivity of the blasts to the differentiative actio n of retinoic acid (RA) both in vivo and in vitro. The mechanism throu gh which PML/RARalpha exerts its biological function remains unknown. However, there is accumulating evidence that it acts by interfering wi th normal endogenous pathways of both RARalpha and PML. The RARalpha r eceptor is implicated in regulating the myeloid differentiation induce d by RA. Although the physiological function of PML is not known, it i s probably a transcription factor. Definition of the molecular archite cture of the t(15;17) has furnished further tools for: (1) molecular d iagnosis of APL and (2) highly sensitive evaluation of the neoplastic clone during antileukaemic therapy. The molecular identification of re sidual APL disease after anti-leukaemia therapy allows patients at ris k of relapse to be identified.