Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Bouska Alyssa, Zhang Weiwei, Sharma Sunandini, Holte Harald, Shah Rauf A, 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, Iqbal Javeed
Аннотация
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) showed that bi-allelic TET2 and DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) propagated in sequential passages, and gene signatures related to T FH and T CM (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.