Retinoic acid in acute promyelocytic leukemia: a model for differentiation therapy.
Acute promyelocytic leukemia is a clonal expansion of malignant cells blocked at a specific stage of myeloid differentiation. The disease is associated with a specific translocation between chromosome 17 and chromosome 15 [t(15;17)] and with a bleeding diathesis previously attributed to disseminated intravascular coagulation, which has recently also been related to primary fibrinolysis. The high percentage of early deaths, about 20%, experienced by acute promyelocytic leukemia patients, is generally due to the hemorrhagic syndrome. A new finding is the high effectiveness of treatment with all-trans retinoic acid, a vitamin A derivative, for inducing complete remission. The induction of cellular maturation by this agent represents the first model of differentiation therapy. Furthermore, recent molecular studies revealed that the breakpoints of the t(15;17) translocation are clustered in the gene of retinoic acid receptor-alpha, generating a hybrid gene product. Gene transfection experiments disclosed the impairment of gene transactivation due to the hybrid gene products, opening new concepts for understanding leukemogenesis. Understanding the mechanisms of action of retinoic acid could extend differentiation therapy to other malignancies with aberrant gene transcription.
Degos
L
L
Institut de Recherches sur les Maladies du Sang, Hôpital Saint-Louis, Paris, France.
D002352:Carrier Proteins / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D015321:Gene Rearrangement / Q000235:genetics; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D008954:Models, Biological; D018168:Receptors, Retinoic Acid; D014212:Tretinoin / Q000627:therapeutic use*
D002352:Carrier Proteins; D018168:Receptors, Retinoic Acid; D014212:Tretinoin