Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute promyelocytic leukemia

Acute promyelocytic leukemia (APL) is associated with chromosomal transloca tions, invariably involving the retinoic acid receptor alpha (RAR alpha) ge ne fused to one of several distinct loci, including the PML or PLZF genes, involved in t(15;17) or t(11;17), respectively. Patients with t(15;17) APL respond well to retinoic acid (RA) and other treatments, whereas those with t(11;17) APL do not. The PML-RAR alpha and PLZF-RAR alpha fusion oncoprote ins function as aberrant transcriptional repressors, in part by recruiting nuclear receptor-transcriptional corepressors and histone deacetylases (HDA Cs). Transgenic mice harboring the RAR alpha fusion genes develop forms of leukemia that faithfully recapitulate both the clinical features and the re sponse to RA observed in humans with the corresponding translocations. Here , we investigated the effects of HDAC inhibitors (HDACIs) in vitro and in t hese animal models. In cells from PLZF-RAR alpha /RAR alpha -PLZF transgeni c mice and cells harboring t(15;17), HDACIs induced apoptosis and dramatic growth inhibition, effects that could be potentiated by RA. HDACIs also inc reased RA-induced differentiation. HDACIs, but not RA, induced accumulation of acetylated histories. Using microarray analysis, we identified genes in duced by RA, HDACIs, or both together. In combination with RA, all HDACIs t ested overcame the transcriptional repression exerted by the RAR alpha fusi on oncoproteins. In vivo, HDACIs induced accumulation of acetylated histori es in target organs. Strikingly, this combination of agents induced leukemi a remission and prolonged survival, without apparent toxic side effects.