β‐Catenin activity induces an RNA biosynthesis program promoting therapy resistance in T‐cell acute lymphoblastic leukemia

• Published in: EMBO molecular medicine 2023-02, Vol.15 (2), p.e16554-n/a
• Main Authors: García‐Hernández, Violeta, Arambilet, David, Guillén, Yolanda, Lobo‐Jarne, Teresa, Maqueda, María, Gekas, Christos, González, Jessica, Iglesias, Arnau, Vega‐García, Nerea, Sentís, Inés, Trincado, Juan L, Márquez‐López, Ian, Heyn, Holger, Camós, Mireia, Espinosa, Lluis, Bigas, Anna
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Antibodies; beta Catenin - metabolism; Biomedicine; Biosynthesis; Cell cycle; Chemotherapy; chemotherapy resistance; Child; Cloning; Datasets; Drug dosages; EMBO03; EMBO18; Genes; Genomes; Humans; Kaiso; LEF/TCF protein; Leukemia; Lymphocytes T; Medical prognosis; Molecular Medicine; Molecular modelling; Mutation; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Protein biosynthesis; Proteins; Rare diseases; Ribonucleic acid; RNA; RNA biosynthesis; RNA processing; T-Lymphocytes - metabolism; Transcription; Transcription Factors - metabolism; T‐ALL; β-Catenin
• ISSN: 1757-4676; 1757-4684
• DOI: 10.15252/emmm.202216554

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‐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 β‐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 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. Synopsis A β‐catenin‐dependent RNA processing program is identified in human T‐ALL cells that is informative for the identification of refractory T‐ALL patients at diagnosis. Inhibition of β‐catenin activity prevents T‐ALL cell recovery and leukemia survival after chemotherapy. β‐catenin is a direct regulator of RNA processing in T‐ALL cells. The β‐catenin‐dependent RNA processing signature predicts response to therapy in T‐ALL patients at diagnosis. Inhibition of β‐catenin in vivo and in vitro improves response to chemotherapy in T‐ALL cells. Graphical Abstract A β‐catenin‐dependent RNA processing program is identified in human T‐ALL cells that is informative for the identification of refractory T‐ALL patients at diagnosis. Inhibition of β‐catenin activity prevents T‐ALL cell recovery and leukemia survival after chemotherapy.