Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma Journal Article
| Authors: | Bouska, A.; Zhang, W.; Sharma, S.; Holte, H.; Shah, R. A.; Lone, W. G.; Soma, M. A.; Yang, R.; Liu, X.; Mehmood, S.; Chawla, R. S.; Cappelli, L. V.; Fiore, D.; Gong, Q.; Heavican-Foral, T. B.; Cannatella, J. J.; Amador, C.; Arif, A.; Smith, L. M.; Lim, S. T.; Ong, C. K.; Feldman, A. L.; Du, M. Q.; Perry, A. M.; de Leval, L.; Greiner, T. C.; Fu, K.; Trøen, G.; Vodák, D.; Nakken, S.; Delabie, J.; Weinstock, D.; Pileri, S.; Laginestra, A.; Kim, K.; Pajvani, U.; Vose, J. M.; Weisenburger, D. D.; Horwitz, S. M.; Dave, S.; Khoury, J.; Inghirami, G.; Chan, W. C.; Iqbal, J. |
| Article Title: | Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma |
| 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. © 2025 The Author(s). American Journal of Hematology published by Wiley Periodicals LLC. |
| Keywords: | cancer genetics; genomics and transcriptomics; lymphomaangioimmunoblastic t-cell lymphoma |
| Journal Title: | American Journal of Hematology |
| ISSN: | 0361-8609 |
| Publisher: | John Wiley & Sons, Inc. |
| Publication status: | Online ahead of print |
| Date Published: | 2025-01-01 |
| Online Publication Date: | 2025-01-01 |
| Language: | English |
| DOI: | 10.1002/ajh.27736 |
| PROVIDER: | scopus |
| DOI/URL: | |
| Notes: | Article -- Source: Scopus |
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