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 (TH2)-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 TH2-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 TH2 differentiation while inhibiting TH1 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

ISSN

2375-2548

Creative Commons License

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

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