ACUTE PROMYELOCYTIC LEUKEMIA - CELLULAR AND MOLECULAR-BASIS OF DIFFERENTIATION AND APOPTOSIS

Acute promyelocytic leukemia (APL) accounts for about 10% of all acute myeloid leukemias and is characterized by the chromosomal translocati on t(15;17), which fuses the retinoic acid receptor (RAR) alpha gene t o the promyelocytic leukemia (PML) gene. The PML-RAR alpha fusion gene plays an important role in leukemogenesis through antagonizing retino ic acid signalling and the regulatory pathways mediated by PML. APL is the first example of a human cancer that can be effectively treated w ith the differentiation inducer all trans retinoic acid (ATRA). The th erapeutic effect of ATRA in APL has been associated with the direct mo dulation of PML-RAR alpha, the restoration of the differentiation path ways regulated by wild-type RAR/retinoid X receptor heterodimer and PM L. More recently, a second drug, arsenic trioxide (As2O3), has been di scovered in China that also has a strong therapeutic effect against AP L. As2O3 can induce clinical remission in de novo or relapsed APL pati ents and has no cross-resistance with ATRA. It has dual effects on APL cells: preferential apoptosis at high concentration (0.5-2 mu M) and partial differentiation at low concentration (0.1-0.5 mu M) Modulation and degradation of PML-RAR alpha proteins can be induced by As2O3 and probably contribute to these two effects. These studies lead to a mod el in which PML-RAR alpha could be the target of both ATRA differentia tion therapy and As2O3 apoptosis therapy. (C) 1997 Elsevier Science In c.