Citations 2
Tcf-1 promotes genomic instability and T cell transformation in response to aberrant β-catenin activation
Arnovitz, Stephen , Mathur, Priya , Tracy, Melissa, Mohsin, Azam , Mondal, Soumi , Quandt, Jasmin , Hernandez, Kyle M. , Khazaie, Khashayarsha , Dose, Marei , Emmanuel, Akinola Olumide , Gounari, Fotini , Gounari, Fotini
Proceedings of the National Academy of Sciences | August 3, 2022 | Volume: 119 | Issue: 32 | Pages: No page available
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 active Wnt/β-catenin signaling.
Wnt/β-catenin activation epigenetically reprograms Regulatory T cells in IBD and progression to dysplasia.
Gounari, Fotini , Quandt, Jasmin , Arnovitz, Stephen , Haghi, Leila, Woehlk, Janine, Moshin, Azam, Emmanuel, Akinola Olumide , Osman, Abu , Krishnan, Manisha, Morin, Samuel B., Weber, Christopher, Khazaie, Khashayarsha , Gounari, Fotini , Mohsin, Azam , Okoreeh, Michael K. , Mathur, Priya, Pearson, Alexander T. , Sweis, Randy F. , Pekow, Joel
No container title available | December 1, 2020 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract The molecular and functional diversity of regulatory T-cells (Tregs) in health and in disease remains unclear. We previously described in colorectal cancer (CRC) patients a subpopulation of RORγt+ Tregs with elevated expression of β-catenin and pro-inflammatory properties. Here we observed progressive expansion of RORγt+ Tregs in inflammatory bowel disease (IBD) patients during inflammation and early dysplasia. Activating Wnt/β-catenin signaling in human and murine Tregs was sufficient to recapitulate the disease-associated increase in frequencies of RORγt+ Tregs expressing IL-17, IFN-γ, and TNFa. We found that binding of the β-catenin interacting partner, TCF-1, to DNA overlapped with Foxp3 binding at enhancer sites of pro-inflammatory pathway genes. Sustained Wnt/β-catenin activation induced newly accessible chromatin sites in these genes and upregulated their expression. These findings indicate that TCF-1 and Foxp3 together limit the expression of pro-inflammatory genes in Tregs. Activation of ꞵ-catenin signaling interferes with this function and promotes the disease-associated RORγt+ Treg phenotype.