All-trans-retinoic acid (RA) treatment induces remissions in acute promyelocytic leukemia (APL) cases expressing the t(15;17) product, promyelocytic leukemia (PML)͞RA receptor ␣ (RAR␣). Microarray analyses previously revealed induction of UBE1L (ubiquitin-activating enzyme E1-like) after RA treatment of NB4 APL cells. We report here that this occurs within 3 h in RA-sensitive but not RA-resistant APL cells, implicating UBE1L as a direct retinoid target. A 1.3-kb fragment of the UBE1L promoter was capable of mediating transcriptional response to RA in a retinoid receptor-selective manner. PML͞RAR␣, a repressor of RA target genes, abolished this UBE1L promoter activity. A hallmark of retinoid response in APL is the proteasome-dependent PML͞RAR␣ degradation. UBE1L transfection triggered PML͞RAR␣ degradation, but transfection of a truncated UBE1L or E1 did not cause this degradation. A tight link was shown between UBE1L induction and PML͞RAR␣ degradation. Notably, retroviral expression of UBE1L rapidly induced apoptosis in NB4 APL cells, but not in cells lacking PML͞RAR␣ expression. UBE1L has been implicated directly in retinoid effects in APL and may be targeted for repression by PML͞ RAR␣. UBE1L is proposed as a direct pharmacological target that overcomes oncogenic effects of PML͞RAR␣ by triggering its degradation and signaling apoptosis in APL cells.