The Notch/Hes1 Pathway Sustains NF-κB Activation through CYLD Repression in T Cell Leukemia

SummaryIt was previously shown that the NF-κB pathway is downstream of oncogenic Notch1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we visualize Notch-induced NF-κB activation using both human T-ALL cell lines and animal models. We demonstrate that Hes1, a canonical Notch target and transcriptional repressor, is responsible for sustaining IKK activation in T-ALL. Hes1 exerts its effects by repressing the deubiquitinase CYLD, a negative IKK complex regulator. CYLD expression was found to be significantly suppressed in primary T-ALL. Finally, we demonstrate that IKK inhibition is a promising option for the targeted therapy of T-ALL as specific suppression of IKK expression and function affected both the survival of human T-ALL cells and the maintenance of the disease in vivo.

► NF-κB activity is active and essential in established Notch-dependent T-ALL leukemias
► Notch through Hes1 sustains NF-κB activity by repressing the deubiquitinase CYLD
► Inhibition of IKK/NFκB activity reduces leukemic load and increases survival in mice