Analysis of the molecular genetics of acute promyelocytic leukemia in mouse models

Abstract

Acute promyelocytic leukemia (APL) is characterized by reciprocal chromosomal translocations that always involve the retinoic acid receptor-α (RARα) gene on chromosome 17. RARα variably fuses to the PML, PLZF, NPM, NuMA, and STAT 5b genes (X genes), leading to the generation of X-RARα and RARα-X fusion genes. The aberrant X-RARα proteins retain the dimerization domains of their parental proteins and therefore can act as dominant negative oncogenic products on both RARα/RXR and X pathways. Studies in transgenic mice harboring X-RARα and RARα-X fusion genes and in mice lacking X genes have helped unravel the molecular mechanisms underlying APL leukemogenesis, which lead to the development of novel therapeutic strategies. Moreover, transgenic mouse models of APL were useful to test in vivo the efficacy of these novel therapeutic approaches as well as of drug combinations such as retinoic acid and As 2O 3 that were previously known to be effective as single agents in human APL.