Beta-catenin deletion and GSK3b inhibition in B-ALL cells
In most cell types, nuclear ß-catenin functions as prominent oncogenic driver and pairs with TCF7-family factors for transcriptional activation of MYC. Surprisingly, B-lymphoid malignancies not only lacked expression and activating lesions of ß-catenin but critically depended on GSK3b for effective b-catenin degradation. Our interactome studies in B-lymphoid tumors revealed that b-catenin formed repressive complexes with lymphoid-specific Ikaros and Lef1 factors at the expense of TCF7. While Lef1 was critical for nuclear ß-catenin translocation, nuclear b-catenin enabled Ikaros-mediated recruitment of nucleosome remodeling and deacetylation (NuRD) complexes for transcriptional repression of MYC. Overall design: To study gene expression changes induced by ß-catenin deletion in B-ALL, BCR-ABL1 transformed Ctnnb1fl/fl cells were transduced with tamoxifen inducible Cre (Cre-ERT2) or control (ERT2) vectors. To induce deletion of ß-catenin, cells were treated with 1µM 4-OHT for two days. For studying changes induced by small molecule induced activation of ß-catenin, cells were treated with 40nM LY2090314 for 1 day. To assess whether ß-catenin deletion reverts the LY2090314-induced transcriptional changes, cells were pre-treated 1µM 4-OHT 1 day before  LY2090314 treatment.