The transcription factor NF-κB is considered the master regulator of the immune response but also acts broadly to regulate gene expression that influences cell survival, proliferation and differentiation. Post-translational modification of NF-κB, phosphorylation in particular, is essential for the transactivation activity of NF-κB. Emerging evidence suggests that the regulation of NF-κB in the nucleus is critical in controlling gene expression. Promyelocytic Leukemia (PML) is a nuclear protein that forms nuclear bodies (PML NBs), sub-nuclear structures that are associated with transcriptionally active genomic regions that have been implicated in multiple processes such as apoptosis, senescence and anti-viral responses. Chromosomal translocations leading to the expression of a PML-retinoic acid receptor-α (PML-RARα) fusion protein are causative for acute promyelocytic leukemia (APL) characterised by a differentiation block at the promyelocytic state of myeloid development. Here we demonstrate that PML is required for phosphorylation of NF-κB p65 and that PML is essential for NF-κB- induced transcriptional responses. Our analysis of available transcriptional profiles of all-trans retinoic acid treated acute promyelocytic leukemia (APL) cells identifies a NF-κB transcriptional programme suppressed by PML-RARα. We further demonstrate that PML-RARα inhibits NF-κB phosphorylation and transcriptional activity. Our findings demonstrate a critical role for PML in promoting NF-κB transcriptional activity which may contribute to APL initiation and maintenance. WT and PML-/- MEFs were analysed for gene expression analysis. Total of 12 samples, inlcluding triplicates were utilized. WT MEFs and PML-/- were stimulated with TNFα for three hours and analysed for gene expresison using unstimulated WT MEFs as control.