ArrayExpress Uploader03599arrayexpress_sid4The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-...20832754E-GEOD-20667/profile/8773/arrayexpressuploader020celldiseaseimmune systemleukemialinenotchDec.12, 2014Falsethe-notchhes1-pathway-sustains-nf-b-activation-thrE-GEOD-20667_A-AFFY-44The Notch/Hes1 pathway sustains NF-κB activation through CYLD repression in T cell leukemiaSep.15, 2014The NF-κB pathway is a critical regulator of the immune system and has been implicated in cellular transformation and tumorigenesis. NF-κB response is regulated by the activation state of the IκB kinase (IKK) complex and triggered by a wide spectrum of stimuli. We previously reported that NF-κB is downstream of Notch1 in T cell acute lymphoblastic leukaemia (T-ALL), however both the mechanisms involving Notch1-induced NF-κB activation and the potential importance of NF-κB in the maintenance of the disease are unknown. Here we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models of this type of leukemia. We show that it is not Notch1 itself but Hes1, a canonical Notch target, the responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by a direct transcriptional repression of the deubiquitinating enzyme CYLD, a well-characterized IKK inhibitor. Consistently, CYLD expression is significantly reduced in primary T-ALL leukemias. Finally, we demonstrate that IKK complex inhibition is a promising option for the targeted therapy of T-ALL as suppression of IKK function affected both the survival of human T-ALL cells in vitro and the maintenance of the disease in vivo. Transcriptional consequences of NF-kB inactivation in human T-ALL1 cell line Twenty samples were analyzed: human T-ALL, CEM, KOPT-K, DND41, HPB-ALL cells lines have been treated at 100uM for 16 hours with control peptide or IKKγ Nemo binding domain (NBD) inhibitory peptide, that specifically block the canonical NF-κB activity by disrupting the interaction of IKKγ to IKKβ and IKKαhttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-20667humanhttp://www.ebi.ac.uk/arrayexpress/experiments/E-GEOD-20667/samples/