Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T‐Cell Lymphoma

作者：Alyssa Bouska, Weiwei Zhang, Sunandini Sharma, Harald Holte, Roshani Shah, Waseem Lone, Mahfuza Afroz Soma, Ruimeng Yang, Xuxiang Liu, Syed Karman Mehmood, Ravneet Singh Chawla, Luca Vincenzo Cappelli, Danilo Fiore, Qiang Gong, Tayla B. Heavican‐Foral, Jeffrey J. Cannatella, Catalina Amador, Aiza Arif, Lynette M. Smith, Soon Thye Lim, Choon Kiat Ong, Andrew L. Feldman, Ming‐Qing Du, Anamarija M. Perry, Laurence de Leval, Timothy C. Greiner, Kai Fu, Gunhild Trøen, Daniel Vodák, Sigve Nakken, Jan Delabie, David M. Weinstock, Stefano Pileri, Antonella Laginestra, KyeongJin Kim, Utpal B. Pajvani, Julie Vose, Dennis D. Weisenburger, Steven M. Horwitz, Sandeep S. Davé, Joseph D. Khoury, Giorgio Inghirami, Wing C. Chan, Javeed Iqbal · 发表于：American Journal of Hematology · 年份：2025 · DOI：10.1002/ajh.27736 · 被引用次数：6 · 研究领域：Lymphoma Diagnosis and Treatment、T-cell and Retrovirus Studies、Viral-associated cancers and disorders

ABSTRACT Nodal follicular helper T‐cell ( T FH ) 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, IDH2 R172 ) and novel ones ( TET3, KMT2D ). TET2, IDH2 R172 , DNMT3A co‐mutated AITLs had poor prognosis ( p < 0.0001). Genes regulating T‐cell receptor (TCR) signaling ( CD28, PLCG1, VAV1 , FYN ) or activation ( RHOA G17V ) 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 , RHOA G17V , IDH2 R172 , 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) sh...