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 translocation t(15;17), which fuses the retinoic acid receptor (RAR) alpha gene to the promyelocytic leukemia (PML) gene. The PML-RAR alpha fusion gene plays an important role in leukemogenesis through antagonizing retinoic acid signalling and the regulatory pathways mediated by PML. APL is the first example of a human cancer that can be effectively treated with the differentiation inducer all trans retinoic acid (ATRA). The therapeutic effect of ATRA in APL has been associated with the direct modulation of PML-RAR alpha, the restoration of the differentiation pathways regulated by wild-type RAR/retinoid X receptor heterodimer and PML. More recently, a second drug, arsenic trioxide (As2O3), has been discovered in China that also has a strong therapeutic effect against APL. As2O3 can induce clinical remission in de novo or relapsed APL patients 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 model in which PML-RAR alpha could be the target of both ATRA differentiation therapy and As2O3 apoptosis therapy. (C) 1997 Elsevier Science Inc.