Retinoid target genes in acute promyelocytic leukemia.
All-trans-retinoic acid (RA)-based differentiation therapy induces clinical remissions in acute promyelocytic leukemia (APL). This has propelled interest in elucidating the molecular mechanisms responsible for these remissions. The t(15;17) rearrangement results in the expression of the PML/RARalpha fusion transcript that is paradoxically linked to the etiology and clinical retinoid response in APL. PML/RARalpha expression blocks terminal myeloid differentiation in APL. Treatment with pharmacological RA dosages overcomes the dominant-negative effects of PML/RARalpha to activate transcription of retinoid target genes. This regulation is linked directly to RA effects in APL, including PML/RARalpha degradation and induction of differentiation. Identifying retinoid target genes is an important step in developing a mechanistic understanding of RA effects in APL. RA target genes have been uncovered through the use of molecular genetic approaches as well as unique cellular and transgenic APL models. Recent developments in the proteomic and functional genomic fields are providing useful tools for elucidating mechanisms of RA response or resistance in APL. These target genes represent potential therapeutic targets in APL and other retinoid-responsive diseases. Previous spotlights in Leukemia have highlighted the importance of cytokine effects and signal transduction crosstalk in retinoid response in APL and in normal hematopoiesis. This review builds on prior work by addressing the role of retinoid target genes in mediating retinoid response or resistance in APL.
Pitha-Rowe
I
I
Department of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, NH 03755, USA.
Petty
W J
WJ
Kitareewan
S
S
Dmitrovsky
E
E
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018390:Gene Targeting; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin