Cooperative role of distinctive TP53 and PTEN combined loss in the peripheral T cell lymphoma–GATA3 molecular subgroup

作者：Waseem Lone, Jiayu Yu, Xuxiang Liu, Dylan T. Jochum, Alyssa Bouska, Kunal Shetty, Tyler A. Herek, Sunandini Sharma, Chengfeng Bi, Ab Rauf Shah, Zaina W. Nasser, Catalina Amador, Aiza Arif, Abdul Rouf Mir, Yuping Li, Tayla B. Heavican‐Foral, Jacob E. Robinson, R. Katherine Hyde, Mamiko Sakata‐Yanagimoto, Satyanarayana Rachagani, Timothy W. McKeithan, David W. Scott, Louis M. Staudt, Giorgio Inghirami, Andrew L. Feldman, Timothy C. Greiner, Julie M. Vose, Lisa M. Rimsza, Joseph D. Khoury, Wing C. Chan, Javeed Iqbal · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.adx6877 · 被引用次数：2 · 研究领域：Lymphoma Diagnosis and Treatment、Viral-associated cancers and disorders、RNA modifications and cancer

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL–not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T H 2)–like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T H 2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase–signal transducer and activator of transcription signaling, promoting T H 2 differentiation while inhibiting T H 1 differentiation. These findings were validated by CRISPR editing of TP53/PTEN loss in human CD4+ T cells and mechanistically evaluated the p53 binding region in intron-3 of GATA3, resulting in transcriptional repression. Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.