Cooperative Role of Distinctive TP53 and PTEN Combined Loss in the Peripheral T Cell Lymphoma-GATA3 Molecular Subgroup

Authors

• Waseem G. Lone, University of Nebraska Medical Center
• Jiayu Yu, University of Nebraska Medical Center
• Xuxiang Liu, University of Nebraska Medical CenterFollow
• Dylan T. Jochum, University of Nebraska Medical CenterFollow
• Alyssa Bouska, University of Nebraska Medical CenterFollow
• Kunal Shetty, City of Hope National Medical Center
• Tyler Herek, University of Nebraska Medical Center
• Sunandini Sharma, University of Nebraska Medical Center
• Chengfeng Bi, University of Nebraska Medical CenterFollow
• Rauf Shah, University of Nebraska Medical CenterFollow
• Zaina W. Nasser, University of Nebraska Medical Center
• Catalina Amador, University of Nebraska Medical Center
• Aiza Arif, University of Nebraska Medical Center
• Abdul Rouf Mir, University of Nebraska Medical CenterFollow
• Yuping Li, City of Hope National Medical Center
• Tayla B. Heavican-Foral, Dana-Farber Cancer Institute
• Jacob Robinson, University of Nebraska at Omaha
• R. Katherine Hyde, University of Nebraska Medical CenterFollow
• Mamiko Sakata-Yanagimoto, University of Tsukuba
• Satyanarayana Rachagani, University of Nebraska Medical Center
• Timothy W. McKeithan, City of Hope National Medical Center
• David W. Scott, British Columbia Cancer
• Louis M. Staudt, National Institutes of Health
• Giorgio Inghirami, Weil Cornell Medical College
• Andrew Feldman, Mayo Clinic College of Medicine
• Timothy Greiner, University of Nebraska Medical Center
• Julie M. Vose, University of Nebraska Medical CenterFollow
• Lisa Rimsza, Mayo Clinic College of Medicine
• Joseph Khoury, University of Nebraska Medical CenterFollow
• Wing C. Chan, City of Hope National Medical Center
• Javeed Iqbal, University of Nebraska Medical CenterFollow
• Lymphoma/Leukemia Molecular Profiling Project (LLMPP)

Document Type

Article

Journal Title

Science Advances

Publication Date

2025

Volume

11

Abstract

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_H2)-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_H2-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_H2 differentiation while inhibiting T_H1 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

MeSH Headings

GATA3 Transcription Factor, Tumor Suppressor Protein p53, PTEN Phosphohydrolase, Animals, Humans, Mice, Lymphoma, T-Cell, Peripheral, Gene Expression Regulation, Neoplastic, Mutation, CD4-Positive T-Lymphocytes

DOI Link

10.1126/sciadv.adx6877

ISSN

2375-2548

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

Recommended Citation

Lone, Waseem G.; Yu, Jiayu; Liu, Xuxiang; Jochum, Dylan T.; Bouska, Alyssa; Shetty, Kunal; Herek, Tyler; Sharma, Sunandini; Bi, Chengfeng; Shah, Rauf; Nasser, Zaina W.; Amador, Catalina; Arif, Aiza; Mir, Abdul Rouf; Li, Yuping; Heavican-Foral, Tayla B.; Robinson, Jacob; Hyde, R. Katherine; Sakata-Yanagimoto, Mamiko; Rachagani, Satyanarayana; McKeithan, Timothy W.; Scott, David W.; Staudt, Louis M.; Inghirami, Giorgio; Feldman, Andrew; Greiner, Timothy; Vose, Julie M.; Rimsza, Lisa; Khoury, Joseph; Chan, Wing C.; Iqbal, Javeed; and Lymphoma/Leukemia Molecular Profiling Project (LLMPP), "Cooperative Role of Distinctive TP53 and PTEN Combined Loss in the Peripheral T Cell Lymphoma-GATA3 Molecular Subgroup" (2025). Journal Articles: Oncology and Hematology. 20.
https://digitalcommons.unmc.edu/com_onchem_articles/20