A ß-catenin-regulated RNA processing transcriptional program imposes chemotherapy resistance and predicts T-ALL patient survival associated with high BRCA1 levels [RNA-Seq]

De novo acquisition or subclonal selection of chemotherapy resistant cell populations are at the base of relapse in cancer. We have now investigated the role of ß-catenin in the evolution of T-ALL patients. We identified an RNA-processing signature that is directly regulated by ß-catenin in T-ALL cell lines. This signature was sufficient to identify T-ALL patients with poorest prognosis, together with high ß-catenin levels in an outdated discovery cohort with high incidence of refractory patients. In an independent validation cohort of T-ALL patients treated with current protocols and a 5-years survival >90%, neither ß-catenin-dependent signatures nor ß-catenin mRNA levels were predictive of patient outcome. However, further analysis of data demonstrated the prognosis value of the ß-catenin RNA-processing signature specifically in tumors carrying high BRCA1 levels. Finally, we show that both ß-catenin and BRCA1 enhanced the recovery of T-ALL cells after chemotherapy thus providing a mechanistic explanation for the prognosis value of ß-catenin and BRCA1. Overall design: 12 RNA-Seq samples (triplicates per condition)