The heterogeneous T-cell neoplasm known as peripheral T-cell lymphomas (PTCLs) is frequently linked to epigenetic instability. For a study, researchers sought to determine novel molecular subtypes of PTCL-not otherwise specified (PTCL-NOS), such as PTCL-GATA3 and PTCL-TBX21, as well as de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, such as angioimmunoblastic T-cell lymphoma.

Inferior overall survival (OS) was seen in DNMT3A-mutated PTCL-TBX21 instances, with DNMT3A-mutated residues biased toward the methyltransferase domain and dimerization motif (S881–R887). The DNMT3A-mutant PTCL-TBX21 patients had significantly enriched transcripts for activated CD8+ T-cell cytotoxic gene signatures, which was subsequently confirmed by immunohistochemistry. Target genes governing interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells, were hypomethylated in DNMT3A-mutant versus wild-type (WT) PTCL-TBX21 patients, according to a genome-wide methylation investigation of these cases.

Similar results were seen in a murine model of PTCL with Dnmt3a deletion, and they were confirmed in vitro by ectopic expression of DNMT3A mutations (DNMT3A-R882, -Q886, and -V716, versus WT) in CD8+ T-cell line, which led to T-cell activation and elevation of EOMES. Additionally, sustained, ectopic production of the DNMT3A mutants led to the preferential expansion of CD8+ T cells with the DNMT3AR882H mutation in primary CD3+ T-cell cultures. The cytotoxic and T-cell memory transcriptional processes linked to the DNMT3AR882H mutation were validated. Single-cell RNA sequencing (RNA-seq) study of CD+ T cells demonstrated differential CD8+ T-cell subset polarization, reflecting results in DNMT3A-mutated PTCL-TBX21.

The results demonstrated the existence of a prognostically significant cytotoxic subgroup in PTCL-TBX21 defined by DNMT3A mutations, which may further clarify the pathological heterogeneity in PTCL-NOS and provide new therapeutic approaches for this subset.