Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation

Stephen Arnovitz, Priya Mathur, Melissa Tracy, Azam Mohsin, Soumi Mondal, Jasmin Quandt, Kyle M. Hernandez, Khashayarsha Khazaie, Marei Dose, Akinola Olumide Emmanuel, Fotini Gounari

Research output: Contribution to journalArticlepeer-review


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 down-regulate genome-stability pathways. Impaired homologous recombination (HR) DNA repair and replication checkpoints lead to retention of DSBs that promote translocations and transformation of double-positive (DP) thymocytes. The resulting lymphomas, which resemble human T cell acute lymphoblastic leukemia (T-ALL), are sensitive to PARP inhibitors (PARPis). 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, PARPis could offer therapeutic options in hematologic malignancies with activeWnt/β-catenin signaling.

Original languageEnglish (US)
Article numbere2201493119
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number32
StatePublished - Aug 9 2022


  • T-ALL
  • Tcf-1
  • genomic instability
  • β-catenin

ASJC Scopus subject areas

  • General


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