3052 – UNCOVERING THE Β-CATENIN-DEPENDENT SIGNATURE IN T-CELL LEUKEMIA INITIATION AND MAINTENANCE

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease comprising up to 25% of all acute leukemia cases. Despite intensive chemotherapy, up to 50% of T-ALL patients fail to achieve a complete remission, making relapse and resistance to therapy the greatest challenge in the treatment of this disease. Activating mutations in Notch are the most prevalent genetic alterations in T-ALL. However, genomic studies suggest that other signaling pathways are also pivotal. We previously showed that β-catenin, a key element in hematopoietic stem cell regulation, is required for T-cell leukemia initiation through Myc transcription modulation downstream of Notch1. To further explore the molecular mechanisms that underlie β-catenin dependent leukemia initiation and maintenance, here we take a comprehensive genomic strategy integrating: 1) the chromatin occupancy of β-catenin and its associated transcription factors TCF and LEF, in T-ALL cell lines by ChIP-Seq, including external data in different models, 2) the transcriptomic map of cells upon β-catenin gene silencing by RNA-Seq, and 3) a gene co-expression network using transcriptome data from public T-ALL primary samples. We identified almost 400 DNA-binding sites located in regulatory regions for β-catenin, co-occupied with TCF and LEF in T-ALL cell lines and, intriguingly, highly enriched for ZBTB33 DNA motif. Interestingly, our data showed a prominent role of β-catenin in regulating RNA processing functions. Also, we further characterize β-catenin modulated genes in different leukemic mouse models. Surprisingly, we detected a low coincidence of β-catenin chromatin binding as compared to human cell lines. Altogether these results allow for a better comprehension of β-catenin activity and its essentiality in T-ALL leukemogenesis, and eventually the opportunity to design β-catenin target therapies for T-ALL treatment.