International Journal of Cell Cloning, Vol 10, 63-69, Copyright © 1992 by AlphaMed Press
All-trans-retinoic acid treatment and retinoic acid receptor alpha gene rearrangement in acute promyelocytic leukemia: a model for differentiation therapy
L Degos
Institut d'Hematologie, Hopital Saint Louis, Paris, France.
All-trans-retinoic acid (ATRA), a vitamin A derivative, is a safe and
effective drug in the obtention of complete remission in acute
promyelocytic leukemia (APL). ATRA is able to activate the maturation of
malignant cells from patients with APL either in vitro or in vivo. Complete
remission was obtained without any feature of aplastic phase and the severe
bleeding diathesis rapidly disappeared. The major adverse effect is the
occurrence of hyperleukocytosis which is prevented by the addition of
chemotherapy. A progressive acquired resistance appears during ATRA
treatment and prolonged event free survival time is obtained after
consolidation with cytotoxic drugs. In APL the retinoic acid receptor alpha
gene is rearranged and fused with a novel gene called PML. The hybrid
PML-RAR product could have a role in the leukemogenesis blocking the effect
of the normal RAR on target genes. Retinoic acid exerts a differentiating
effect either by the induction of a normal activity of the aberrant product
in the presence of pharmacological concentration, or by an over-expression
of the normal allele. The results obtained by cellular and molecular
biology gave opportunities to confirm the diagnosis, to follow the
assessment of the minimal residual disease and to understand the acquired
resistance.
