Abstract Text: Understanding the mechanisms promoting chromosomal translocations of the rearranging receptor loci in leukemia and lymphoma remains incomplete. Here we show that leukemias induced by aberrant activation of β-catenin in thymocytes, which bear recurrent Tcra/Myc-Pvt1 translocations, depend on Tcf-1. The DNA double-strand breaks (DSBs) in the Tcra site of the translocation are Rag-generated whereas the Myc-Pvt1 DSBs are not. Aberrantly activated β-catenin redirects Tcf-1-binding to novel DNA-sites to alter chromatin accessibility and downregulate genome-stability pathways. Impaired homologous recombination DNA-repair and replication-checkpoints lead to retention of DSBs that promote translocations and transformation of DP thymocytes. The resulting lymphomas, which resemble human T-ALL, are sensitive to PARP inhibitors (PARPi). Our findings indicate that aberrant β-catenin signaling contributes to translocations in thymocytes by guiding Tcf-1 to promote the generation and retention of replication induced DSBs allowing their coexistence with Rag-generated DSBs. Thus, PARPi could offer therapeutic options in hematologic malignancies with active Wnt/β-catenin signaling.
