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 microM) and partial differentiation at low concentration (0.1-0.5 microM). 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.
Chen
Z
Z
Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, China.
Wang
Z Y
ZY
Chen
S J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy / Q000235:genetics; D010087:Oxides / Q000008:administration & dosage / Q000627:therapeutic use; D014178:Translocation, Genetic / Q000235:genetics; D014212:Tretinoin / Q000008:administration & dosage / Q000627:therapeutic use
D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide