DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS

作者：Tyler A. Herek, Alyssa Bouska, Waseem Lone, Sunandini Sharma, Catalina Amador, Tayla B. Heavican, Yuping Li, Wei Qi, Dylan T. Jochum, Timothy C. Greiner, Lynette M. Smith, Stefano Pileri, Andrew L. Feldman, Andreas Rosenwald, German Ott, Soon Thye Lim, Choon Kiat Ong, Joo Y. Song, Elaine S. Jaffe, Gang Greg Wang, Louis M. Staudt, Lisa M. Rimsza, Julie M. Vose, Francesco d’Amore, Dennis D. Weisenburger, Wing C. Chan, Javeed Iqbal · 发表于：Blood · 年份：2022 · DOI：10.1182/blood.2021015019 · 被引用次数：48 · 研究领域：Acute Myeloid Leukemia Research、Lymphoma Diagnosis and Treatment、Epigenetics and DNA Methylation

Peripheral T-cell lymphomas (PTCLs) are heterogenous T-cell neoplasms often associated with epigenetic dysregulation. We investigated de novo DNA methyltransferase 3A (DNMT3A) mutations in common PTCL entities, including angioimmunoblastic T-cell lymphoma and novel molecular subtypes identified within PTCL-not otherwise specified (PTCL-NOS) designated as PTCL-GATA3 and PTCL-TBX21. DNMT3A-mutated PTCL-TBX21 cases showed inferior overall survival (OS), with DNMT3A-mutated residues skewed toward the methyltransferase domain and dimerization motif (S881-R887). Transcriptional profiling demonstrated significant enrichment of activated CD8+ T-cell cytotoxic gene signatures in the DNMT3A-mutant PTCL-TBX21 cases, which was further validated using immunohistochemistry. Genomewide methylation analysis of DNMT3A-mutant vs wild-type (WT) PTCL-TBX21 cases demonstrated hypomethylation in target genes regulating interferon-γ (IFN-γ), T-cell receptor signaling, and EOMES (eomesodermin), a master transcriptional regulator of cytotoxic effector cells. Similar findings were observed in a murine model of PTCL with Dnmt3a loss (in vivo) and further validated in vitro by ectopic expression of DNMT3A mutants (DNMT3A-R882, -Q886, and -V716, vs WT) in CD8+ T-cell line, resulting in T-cell activation and EOMES upregulation. Furthermore, stable, ectopic expression of the DNMT3A mutants in primary CD3+ T-cell cultures resulted in the preferential outgrowth of CD8+ T cells with DNMT3AR882H mutation. Sing...