Retinoic acid and acute promyelocytic leukemia: a model of targetting treatment for human cancer.
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.
Chen
Z
Z
Shanghai Institute of Hematology, Rui Jin Hospital, Shanghai Second Medical University, P.R. China.
Chen
S J
SJ
Wang
Z Y
ZY
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*
D018168:Receptors, Retinoic Acid; D014212:Tretinoin