β-Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T-cell acute lymphoblastic leukemia
García-Hernández V, Arambilet D, Guillén Y, Lobo-Jarne T, Maqueda M, Gekas C, González J, Iglesias A, Vega-García N, Sentís I, Trincado JL, Márquez-López I, Heyn H, Camós M, Espinosa L, Bigas A.
EMBO MOL MED
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 beta-catenin/CTNNB1 in the evolution of T-cell Acute Lymphoblastic Leukemia (T-ALL) patients and its involvement in therapy resistance. We have identified a specific gene signature that is directly regulated by beta-catenin, TCF/LEF factors and ZBTB33/Kaiso in T-ALL cell lines, which is highly and significantly represented in five out of six refractory patients from a cohort of 40 children with T-ALL. By subsequent refinement of this gene signature, we found that a subset of beta-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 beta-catenin in RNA and protein synthesis in T-ALL and provide in vitro and in vivo experimental evidence that beta-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 beta-catenin inhibitors will enhance chemotherapy response and prevent disease relapse in T-ALL patients.
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