Cooperative role of distinctive TP53 and PTEN combined loss in the peripheral T cell lymphoma–GATA3 molecular subgroup
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<sub>H</sub>2)-like differentiation and poor prognosis, has frequent co-occurrence of <i>TP53</i> loss/mutation and heterozygous <i>PTEN</i> loss. CD4+ T cell conditional mouse models with <i>Trp53</i> mutation/deletion and <i>Pten</i> loss demonstrated mature T cell lymphomas (mTCLs) with T<sub>H</sub>2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of <i>Trp53/Pten</i> induced T cell receptor and Janus kinase-signal transducer and activator of transcription signaling, promoting T<sub>H</sub>2 differentiation while inhibiting T<sub>H</sub>1 differentiation. These findings were validated by CRISPR editing of <i>TP53/PTEN</i> 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.
Authors
- Satyanarayana Rachagani (ORCID: https://orcid.org/0000-0003-3949-8566)
- Giorgio Inghirami (ORCID: https://orcid.org/0000-0001-5566-0864)
- Chengfeng Bi (ORCID: https://orcid.org/0000-0001-5375-7515)
- Mamiko Sakata‐Yanagimoto (ORCID: https://orcid.org/0000-0001-7310-8045)
- Lisa M. Rimsza (ORCID: https://orcid.org/0000-0003-1268-2750)
- Wing C. Chan (ORCID: https://orcid.org/0000-0002-6243-6008)
- Sunandini Sharma (ORCID: https://orcid.org/0009-0005-4311-7924)
- R. Katherine Hyde (ORCID: https://orcid.org/0000-0003-2808-1749)
- Tyler A. Herek
- David W. Scott (ORCID: https://orcid.org/0000-0002-0435-5947)
- Timothy W. McKeithan (ORCID: https://orcid.org/0000-0003-2242-3074)
- Xuxiang Liu (ORCID: https://orcid.org/0000-0002-1677-0814)
- Louis M. Staudt (ORCID: https://orcid.org/0000-0002-1735-2892)
- Ab Rauf Shah (ORCID: https://orcid.org/0000-0002-5779-154X)
- Abdul Rouf Mir (ORCID: https://orcid.org/0000-0002-2897-4419)
- Timothy C. Greiner (ORCID: https://orcid.org/0000-0003-1470-8328)
- Tayla B. Heavican‐Foral (ORCID: https://orcid.org/0000-0002-8384-6217)
- Javeed Iqbal (ORCID: https://orcid.org/0000-0003-3668-0629)
- Dylan T. Jochum (ORCID: https://orcid.org/0000-0003-2750-6741)
- Jacob E. Robinson (ORCID: https://orcid.org/0000-0002-7835-6619)
- Catalina Amador (ORCID: https://orcid.org/0000-0003-0352-5526)
- Julie M. Vose (ORCID: https://orcid.org/0000-0003-1015-7434)
- Aiza Arif
- Joseph David Khoury (ORCID: https://orcid.org/0000-0003-2621-3584)
- Alyssa Bouska (ORCID: https://orcid.org/0000-0003-1324-6678)
- Andrew L. Feldman (ORCID: https://orcid.org/0000-0001-5009-4808)
- Yuping Li (ORCID: https://orcid.org/0000-0002-6514-6719)
- Jiayu Yu (ORCID: https://orcid.org/0000-0003-2573-8741)
- Kunal Shetty (ORCID: https://orcid.org/0000-0003-1065-2734)
- Waseem Lone (ORCID: https://orcid.org/0000-0003-3078-614X)
- Zaina W. Nasser
Institutions
- University of Nebraska at Omaha (US)
- National Institutes of Health (US)
- City Of Hope National Medical Center (US)
- Mayo Clinic (US)
- University of Miami (US)
- University of Tsukuba (JP)
- Cornell University (US)
- Dana-Farber Cancer Institute (US)
- Mayo Clinic in Arizona (US)
- National Cancer Institute (US)
- University of Nebraska Medical Center (US)
Publication Details
- Journal
- Science Advances
- Published
- 2025-10-17
- DOI
- https://doi.org/10.1126/sciadv.adx6877
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00