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

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 <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_H2-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_H2 differentiation while inhibiting T_H1 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.