GSE69156
ChIP-Sequencing experiment for N1IC and ß-Catenin in Jurkat T-ALL cells.
Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. Using multiple in vivo and in vitro T-ALL models we here demonstrate that ß-Catenin is essential for Notch-driven T-cell leukemic initiation. Transcriptome analyses of leukemic initiating cells revealed a switch in ß-Catenin activity that was Notch-context dependent. Moreover, ChIP-seq coupled with RNA-Seq in human Notch-active T-ALL showed that leukemic ß-Catenin was independent of canonical LEF/TCF partners, and instead depended on direct association with Notch or ZBTB33/Kaiso for gene activation. The functional relevance of this mechanism is exemplified by the MYC 3´enhancer that requires ß-Catenin and Notch1 recruitment to induce MYC expression. Finally, we demonstrate that pharmacological inhibition of ß-Catenin with PKF115-584 prevented and partially reverted leukemogenesis induced by active Notch1. Overall design: Examination of chromatin immunprecipitated with antibodies against 2 transcription factors (N1IC and ß-Catenin) in Jurkat T-ALL cells.