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

Garcia-Hernandez, V.; Arambilet, D.; Guillen, Y.; Lobo, T.; Gekas, C.; Vega-Garcia, N.; Sentis, I.; Trincado, J. L.; Marquez-Lopez, I.; Heyn, H.; Camos, M.; Espinosa, L.; Bigas, A.

doi:10.1101/2022.07.07.499249

bioRxiv · 10.1101/2022.07.07.499249

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

Garcia-Hernandez, V.·Arambilet, D.·Guillen, Y.·Lobo, T.·Gekas, C.·Vega-Garcia, N.·Sentis, I.·Trincado, J. L.·Marquez-Lopez, I.·Heyn, H.·Camos, M.·Espinosa, L.·Bigas, A.

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Abstract

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-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 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 {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 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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Garcia-Hernandez, V., Arambilet, D., Guillen, Y., Lobo, T., Gekas, C., Vega-Garcia, N., Sentis, I., Trincado, J. L., Marquez-Lopez, I., Heyn, H., Camos, M., Espinosa, L., Bigas, A.. 2022-07-09. β-catenin activity induces an RNA biosynthesis program promoting therapy resistance in T Acute Lymphoblastic Leukemia. https://doi.org/10.1101/2022.07.07.499249

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