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 -Catenin is essential for Notch-driven T-cell leukemic initiation. Transcriptome analyses of leukemic initiating cells revealed a switch in -Catenin activity that was Notch-context dependent. Moreover, ChIP-seq coupled with RNA-Seq in human Notch-active T-ALL showed that leukemic -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 3enhancer that requires -Catenin and Notch1 recruitment to induce MYC expression. Finally, we demonstrate that pharmacological inhibition of -Catenin with PKF115-584 prevented and partially reverted leukemogenesis induced by active Notch1. SOURCE: Christos Gekas (christos.gekas@gmail.com) -  Centre for Genomic Regulation (CRG)

Pluto Bioinformatics

GSE69157: RNA-Sequencing experiment for effects of PKF115-584 treatment on four T-ALL cell lines (RPMI8402, HPB-ALL, Jurkat, CCRF-CEM).