@article{c2c91c9f54704e94b396b79f1f4134f9,
title = "DNMT3A mutations define a unique biological and prognostic subgroup associated with cytotoxic T cells in PTCL-NOS",
abstract = "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. Single-cell RNA sequencing(RNA-seq) analysis of CD3+ T cells revealed differential CD8+ T-cell subset polarization, mirroring findings in DNMT3A-mutated PTCL-TBX21 and validating the cytotoxic and T-cell memory transcriptional programs associated with the DNMT3AR882H mutation. Our findings indicate that DNMT3A mutations define a cytotoxic subset in PTCL-TBX21 with prognostic significance and thus may further refine pathological heterogeneity in PTCL-NOS and suggest alternative treatment strategies for this subset.",
author = "Herek, {Tyler A.} and Alyssa Bouska and Waseem Lone and Sunandini Sharma and Catalina Amador and Heavican, {Tayla B.} and Yuping Li and Qi Wei and Dylan Jochum and Greiner, {Timothy C.} and Lynette Smith and Stefano Pileri and Feldman, {Andrew L.} and Andreas Rosenwald and German Ott and Lim, {Soon Thye} and Ong, {Choon Kiat} and Joo Song and Jaffe, {Elaine S.} and Wang, {Gang Greg} and Louis Staudt and Rimsza, {Lisa M.} and Julie Vose and Francesco d'Amore and Weisenburger, {Dennis D.} and Chan, {Wing C.} and Javeed Iqbal",
note = "Funding Information: The authors thank the University of Nebraska Medical Center Human Genetics Laboratory at the Munroe-Meyer Institute, the University of Nebraska DNA Sequencing Core, The University of Nebraska Medical Center Flow Cytometry Core, the Genomic Core Facility at City of Hope, SingHealth Tissue Repository, Advanced Molecular Pathology Laboratory at SingHealth, and Duke–National University of Singapore (NUS) Genome Biology Facility. The authors also thank Francoise Berger for the contribution of cases to the International Peripheral T-Cell Lymphoma Consortium. This work would not be possible without the support provided by the National Institutes of Health (NIH), National Cancer Institute (NCI) grants UH2 CA206127-02 (J.I. and W.C.C.) and P01 CA229100 (L.M.R. J.I. and W.C.C.), the Leukemia and Lymphoma Society (TRP-6129-04 [J.I.]), and NIH NCI Eppley Cancer Center Support grant P30 CA036727 (J.I.), NIH NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) II 5 UO1 CA157581-01 (W.C.C.), NIH NCI Specialized Programs of Research Excellence 1P50 CA136411-01 01A1 PP-4 (W.C.C.), City of Hope internal funds (W.C.C.), and AIRC 5x1000 grant (n. 21198 [S.P.]). T.A.H. is supported by the University of Nebraska Medical Center NIH training grant (5T32CA009476-23). The University of Nebraska DNA Sequencing Core receives support from the National Institute for General Medical Science (NIGMS) IDeA Networks of Biomedical Research Excellence (P20GM103427-14) and the Centers of Biomedical Research Excellence (1P30GM110768-01) grants, as well as The Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727). Funding Information: This work would not be possible without the support provided by the National Institutes of Health (NIH), National Cancer Institute (NCI) grants UH2 CA206127-02 (J.I. and W.C.C.) and P01 CA229100 (L.M.R., J.I., and W.C.C.), the Leukemia and Lymphoma Society (TRP-6129-04 [J.I.]), and NIH NCI Eppley Cancer Center Support grant P30 CA036727 (J.I.), NIH NCI Strategic Partnering to Evaluate Cancer Signatures (SPECS) II 5 UO1 CA157581-01 (W.C.C.), NIH NCI Specialized Programs of Research Excellence 1P50 CA136411-01 01A1 PP-4 (W.C.C.), City of Hope internal funds (W.C.C.), and AIRC 5x1000 grant (n. 21198 [S.P.]). T.A.H. is supported by the University of Nebraska Medical Center NIH training grant (5T32CA009476-23). The University of Nebraska DNA Sequencing Core receives support from the National Institute for General Medical Science (NIGMS) IDeA Networks of Biomedical Research Excellence (P20GM103427-14) and the Centers of Biomedical Research Excellence (1P30GM110768-01) grants, as well as The Fred & Pamela Buffett Cancer Center Support Grant (P30CA036727). Publisher Copyright: {\textcopyright} 2022 American Society of Hematology",
year = "2022",
month = sep,
day = "15",
doi = "10.1182/blood.2021015019",
language = "English (US)",
volume = "140",
pages = "1278--1290",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "11",
}