Document Type
Article
Journal Title
American Journal of Hematology
Publication Date
2025
Abstract
Nodal follicular helper T-cell (TFH) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole-exome sequencing (n = 124), transcriptomic (n = 78), and methylation (n = 40) analysis, we identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2R172) and novel ones (TET3, KMT2D). TET2, IDH2R172, DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOAG17V) or regulators of the PI3K-pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2) were mutated. CD28 mutation/fusion was associated with poor prognosis (p = 0.02). WES of purified, neoplastic T-cell (CD3+PD1+) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non-lymphoid cells, but other mutations (CD28, RHOAG17V, IDH2R172, PLCG1) in neoplastic cells. Integrated DNA-methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K-signaling, and apoptosis. RNA-seq analysis identified fusion transcripts regulating TCR-activation (8%), revealed a restricted TCR-repertoire (α = 87%, β = 72%), and showed the presence of Epstein-Barr virus transcriptome (73%). GEP demonstrated the association of B-cells or dendritic cells in the tumor milieu with prognosis (p < 0.01). RNA-seq and WES analysis of 12 AITL-patient-derived-xenografts (PDX) showed that bi-allelic TET2 and DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to TFH and TCM (central-memory) were well-maintained through passages. Gene expression signatures associated with late PDX passages (3rd-5th) were enriched with proliferation and metabolic reprogramming-related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis (p = 0.05) and engineered PHLPP2 or TET2 loss in CD4+ T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.
DOI Link
ISSN
1096-8652
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
Recommended Citation
Bouska, Alyssa; Zhang, Weiwei; Sharma, Sunandini; Holte, Harald; Shah, Rauf; Lone, Waseem G.; Soma, Mahfuza Afroz; Yang, Ruimeng; Liu, Xuxiang; Mehmood, Syed; Chawla, Ravneet Singh; Cappelli, Luca Vincenzo; Fiore, Danilo; Gong, Qiang; Heavican-Foral, Tayla B.; Cannatella, Jeffrey J.; Amador, Catalina; Arif, Aiza; Smith, Lynette M.; Lim, Soon Thye; Ong, Choon Kiat; Feldman, Andrew L.; Du, Ming-Qing; Perry, Anamarija M.; de Leval, Laurence; Greiner, Timothy C.; Fu, Kai; Trøen, Gunhild; Vodák, Daniel; Nakken, Sigve; Delabie, Jan; Weinstock, David; Pileri, Stefano; Laginestra, Antonella; Kim, KyeongJin; Pajvani, Utpal; Vose, Julie M.; Weisenburger, Dennis D.; Horwitz, Steven M.; Dave, Sandeep; Khoury, Joseph; Inghirami, Giorgio; Chan, Wing C.; and Iqbal, Javeed, "Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma" (2025). Journal Articles: Oncology and Hematology. 19.
https://digitalcommons.unmc.edu/com_onchem_articles/19
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