2002 Volume 16 Issue 2 Pages 50-61
Acute promyelocytic leukemia (APL) is a distinct subtype of leukemia characterized hematologically with maturation blockade at the stage of promyelocytes; cytogenetically with chromosome translocation involving 17q21, which generates retinoic acid receptor-α (RARα) chimeric gene; and clinically with differentiation-induction therapy with all-trans retinoic acid (ATRA). The genetic abnormality in APL exclusively disrupts theRARα gene by forming X-RARα, whereas the partner X-gene diversely involves PML in most patients and thePLZF, NPM, NuMA, or Stat5b gene in a few. Because X-RARα invariably has the DNA-binding and ligand-binding domains of RAR a, X-RARa inhibits in a dominant negative fashion the function of RARα as aRA-dependent transcription factor. In in vivo models, transgenic mice with PML-RARα or PLZF-RARαdevelop leukemia resembling APL, although an allelic inactivation of the X-gene may also play a role in the leukemogenesis of APL. It is interesting that the mechanism by which PML-RARα causes APL may also underlie differentiation-induction of APL with ATRA. In response to ATRA at pharmacological doses, PML-RARα releases corepressors and the histone deacetylase (HDAC) complex and recruits coactivators, which leads to a restoration of RA-responsive gene transcription. However, APL patients often acquire ATRA-resistance at relapse, which may be caused by acquired mutations in the RARα/E-domain of the PML-RARα gene. Therapy with arsenic acid or HDAC inhibitor may be of clinical use for refractory APL, and further investigation is needed.
