RARA fusion genes in acute promyelocytic leukemia: a review.
The t(15;17)(q24;q21), generating a PML-RARA fusion gene, is the hallmark of acute promyelocytic leukemia (APL). At present, eight other genes fusing with RARA have been identified. The resulting fusion proteins retain domains of the RARA protein allowing binding to retinoic acid response elements (RARE) and dimerization with the retinoid X receptor protein (RXRA). They participate in protein-protein interactions, associating with RXRA to form hetero-oligomeric complexes that can bind to RARE. They have a dominant-negative effect on wild-type RARA/RXRA transcriptional activity. Moreover, RARA fusion proteins can homodimerize, conferring the ability to regulate an expanded repertoire of genes normally not affected by RARA. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of ATRA or arsenic trioxide. However, resistance to these two drugs is a major problem, which necessitates development of new therapies.
Laboratoire d'Histologie, Embryologie et Cytogénétique, Faculté de Médecine et des Sciences de la Santé, Université de Brest, Brest, France.
Etienne
E
De Braekeleer
Nathalie
N
Douet-Guilbert
Marc
M
De Braekeleer
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002869:Chromosome Aberrations; D050939:Gene Fusion; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D020218:Response Elements; D000072482:Retinoic Acid Receptor alpha
C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha
RARA; acute promyelocytic leukemia; chromosomal aberrations; fusion genes; treatment