Cooperative role of distinctive TP53 and PTEN combined loss in the peripheral T cell lymphoma–GATA3 molecular subgroup
- Waseem G. Lone
- Jiayu Yu
- Xuxiang Liu
- Dylan T. Jochum
- Alyssa Bouska
- Kunal Shetty
- Tyler Herek
- Sunandini Sharma
- Chengfeng Bi
- Rauf Shah
- Zaina W. Nasser
- Catalina Amador
- Aiza Arif
- Abdul Rouf Mir
- Yuping Li
- Tayla B. Heavican-Foral
- Jacob Robinson
- R. Katherine Hyde
- Mamiko Sakata-Yanagimoto
- Satyanarayana Rachagani
- Timothy W. McKeithan
- David W. Scott
- Louis M. Staudt
- Giorgio Inghirami
- Andrew Feldman
- Timothy Greiner
- Julie M. Vose
- Lisa Rimsza
- Joesph Khoury
- Wing C. Chan
- Javeed Iqbal
2025-10-17
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.