ARSENIC AND RETINOIC ACID, TOWARDS ONCOGE NE-TARGETED TREATMENTS OF ACUTE PROMYELOCYTIC LEUKEMIA

Acute promyelocytic leukaemia is a key model system in cancer biology. Its exquisite sensitivity to retinoic acid constitutes the first exam ple of differentiation therapy. The PML/RAR alpha fusion protein gener ated by the t(15; 17) translocation is the molecular basis of transfor mation. PML/RAR alpha induces transformation most likely through a dom inant negative interference with the function of nuclear receptors lea ding to a differentiation block. The fusion protein also delocalises P ML and other nuclear body antigens and this alteration of nuclear prot ein trafic seems to play a role in growth control and apoptosis. The c linical response of this disease to retinoids and arsenic trioxide, bo th of which induce the degradation of the fusion protein, constitute t he first example of a therapy directly targeted to a specific genetic lesion in a human cancer.