Forced retinoic acid receptor α homodimers prime mice for APL-like leukemia

RARA becomes an acute promyelocytic leukemia (APL) oncogene by fusion with any of five translocation partners. Unlike RAR alpha, the fusion proteins homodimerize, which may be central to oncogenic activation. This model was tested by replacing PML with dimerization domains from p50NF kappa B (p50-RAR alpha) or the rapamycin-sensitive dimerizing peptide of FKBP12 (F3RAR alpha). The X-RAR alpha fusions recapitulated in vitro activities of PML-RAR alpha. For FZI-RAR alpha, these properties were rapamycin sensitive. Although in vivo the artificial fusions alone are poor initiators of leukemia, p5O-RAR alpha readily cooperates with an activated mutant CDw131 to induce APL-like disease. These results demonstrate that the dimerization interface of RAR alpha fusion partners is a critical element in APL pathogenesis while pointing to other features of PML for enhancing penetrance and progression.