ATRA(ouble) in the treatment of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is a unique disease that responds to differentiation-inducing effects of all-trans-retinoic acid (ATRA). ATRA induces complete clinical remissions (CRs) in most patients and now constitutes a standard therapy in patients with APL. However, CRs induced by ATRA are usually brief, and resistance to the therapy rapidly develops, leading to relapses in almost every patient; thus limiting the use of ATRA as a single agent. On the basis of clinical and in vitro studies, the following mechanisms have been proposed to explain ATRA resistance: 1) induction of accelerated metabolism of ATRA, 2) increased expression of cellular retinoic acid-binding proteins (CRABPs), 3) constitutive degradation of PML-RAR alpha, 4) point mutations in the ligand-binding domain of RAR alpha of PML-RAR alpha, 5) P-glycoprotein expression, 6) transcriptional repression by histone deacetylase activity, 7) isoforms of PML-RAR alpha, 8) persistent telomerase activity, and 9) expression of type II transglutaminase. In this review, we discuss the evidence provided in support of each mechanism, the mechanism's possible impact on the outcome of APL, and the newer approaches that are being employed to overcome ATRA resistance.