title: Retinoic acid and acute promyelocytic leukemia: a model of targetting treatment for human cancer.
abstract: Acute promyelocytic leukemia (APL) is the first example among the human malignancies that responds to differentiation therapy, in that complete remission (CR) can be achieved in up to 90% of patients by using a differentiation inducer, all-trans retinoic acid (ATRA). The specific chromosomal translocation t(15;17) in APL has been shown to fuse the gene for the retinoic acid receptor alpha (RAR alpha) with a chromosome 15q locus, PML. Alterations to the RAR alpha and the PML gene structures in the t(15;17) have been characterized and used as specific molecular marker for diagnosis of the disease. PML/RAR alpha antagonizes wild-type PML and RXR and could block the differentiation pathways mediated by these two regulators. A variant translocation t(11;17) has also been discovered in a subset of APL which fuses RAR alpha to a new gene, PLZF on chromosome 11q23. Both PML/RAR alpha and PLZF/RAR alpha display the "dominant negative" effect on the wild-type RAR/RXR. However, t(11;17) APL patients differ from t(15;17) APL in that they respond poorly to ATRA. Morphologically defined APL cases which however do not have PML/RAR alpha generally show no response to ATRA. Recently it has been shown that PML/RAR alpha can be modulated directly by ATRA. All these data support the idea that PML/RAR alpha is a specific target of ATRA which can overcome the differentiation block imposed by PML/RAR alpha. The ATRA treatment of APL thus further reinforces the concept of differentiation therapy.
authors.affiliation: Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, P.R. China.
authors.forename: Z
authors.initials: Z
authors.lastname: Chen
authors.forename: S J
authors.initials: SJ
authors.lastname: Chen
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Wang
mesh_terms: D018390:Gene Targeting; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D014178:Translocation, Genetic; D014212:Tretinoin / Q000627:therapeutic use*
chemical_list: D018168:Receptors, Retinoic Acid; D014212:Tretinoin