β-catenin activity induces an RNA biosynthesis program promoting therapy resistance in T Acute Lymphoblastic Leukemia

Understanding the molecular mechanisms that contribute to the appearance of chemotherapy resistant cell populations is necessary to improve cancer treatment. We have now investigated the role of β-catenin/CTNNB1 in the evolution of T-Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by β-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in 5 out of 6 refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of β-catenin target genes involved with RNA-processing function are sufficient to segregate T-ALL refractory patients in three independent cohorts. We demonstrate the implication of β-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that β-catenin is crucial for the cellular response to chemotherapy, mainly in the cellular recovery phase after treatment. We propose that combination treatments involving chemotherapy plus β-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients. ChIPseq experiments: For b-catenin: RPMI8402 cell line: n=5 for R&D antibody in basal conditions, n =2 for R&D antibody upon LiCl treatment, n=2 for SC antibody in basal conditions, n=2 for SC antibody upon LiCl treatment. For Jurkat cell line: n=3 for R&D antibody in basal conditions in the Jurkat cell line. For TCF1,LEF1,Kaiso: precipitating TCF1 (n=3), LEF1 (n=3) and Kaiso (n=3) in RPMI8402 For RNA-seq experiments in RPMI8402:RNAseq analysis of sh-β-catenin vs sh-control (n=3 for each condition). For H3Ac in RPMI in basal conditions (n=2) and LiCl treated (n=2)