期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：32
DOI：10.1073/pnas.2201493119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Lymphoid malignancies frequently bear oncogenic chromosomal translocations of the rearranging immune receptor loci; however, the predisposing mechanisms remain unclear. Using a clinically relevant model of T cell leukemia driven by β-catenin activation, our studies show that β-catenin exploits Tcf-1 to promote a novel transcriptional and epigenetic state that down-regulates both homologous recombination (HR) DNA repair and cell cycle regulatory pathways, which promote
Tcra/Myc-Pvt1 translocations. Significantly, the HR impairments of these leukemias render them highly sensitive to PARP inhibitors, a finding that could inform future therapeutic options for malignancies with activated β-catenin signaling.
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.
