Oncogenes and tumor suppressors in the molecular pathogenesis of acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is associated with reciprocal chromosomal translocations always involving the retinoic acid receptor a (RAR alpha) gene on chromosome 17 and variable partner genes (X genes) on distinct chromosomes. RARa fuses to the PML gene in the vast majority of APL cases, and in a few cases to the PLZF, NPM, NuMA and Stat5b genes, respectively, leading to the generation of RAR alpha -X and X-RAR alpha fusion genes. Both fusion proteins can exert oncogenic functions through their ability to interfere with the activities of X and RARa proteins. Here, it will be discussed in detail how an extensive biochemical analysis as well as a systematic in vivo genetic approach in the mouse has allowed the definition of the multiple oncogenic activities of PML-RAR alpha, and how it has become apparent that this oncoprotein is able to impair RARa at the transcription level and the tumor suppressive function of the PML protein.