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

Nodal follicular helper T-cell (T <sub>FH</sub>) 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 <sup>R172</sup> ) and novel ones (TET3, KMT2D). TET2, IDH2 <sup>R172</sup> , DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA <sup>G17V</sup> ) 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<sup>+</sup>PD1<sup>+</sup>) 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 <sup>G17V</sup> , IDH2 <sup>R172</sup> , 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 <sub>FH</sub> and T <sub>CM</sub> (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<sup>+</sup> T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.

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Publication Details

Journal
American Journal of Hematology
Published
2025-06-13
DOI
https://doi.org/10.1002/ajh.27736
Citations
4
Primary Topic
Lymphoma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
5.89

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article

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

Kai Fu, Ming‐Qing Du, Giorgio Inghirami, Gunhild Trøen et al.
4 citations
American Journal of Hematology
Lymphoma Diagnosis and Treatment
5.89
article

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

Kai Fu, Ming‐Qing Du, Giorgio Inghirami, Gunhild Trøen, Jeffrey J. Cannatella, Ruimeng Yang, Utpal B. Pajvani, Danilo Fiore, Sunandini Sharma, Rakesh Chawla, Xuxiang Liu, Anamarija M. Perry, David M. Weinstock, Luca Vincenzo Cappelli, Sigve Nakken, Antonella Laginestra, Soon Thye Lim, Lynette M. Smith, Stefano Pileri, Timothy C. Greiner, Daniel Vodák, KyeongJin Kim, Tayla B. Heavican‐Foral, Javeed Iqbal, Roshani Shah, Syed Karman Mehmood, Mahfuza Afroz Soma, Steven M. Horwitz, Choon Kiat Ong, Laurence de Leval, Qiang Gong, Jan Delabie, Aiza Arif, Sandeep S. Davé, Harald Holte, Joseph David Khoury, Alyssa Bouska, Andrew L. Feldman, Weiwei Zhang, Catalina Amador, Wing C. Chan, Julie Vose, Waseem Lone, Dennis D. Weisenburger
article en
4 citations

Abstract

Nodal follicular helper T-cell (T <sub>FH</sub>) 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 <sup>R172</sup> ) and novel ones (TET3, KMT2D). TET2, IDH2 <sup>R172</sup> , DNMT3A co-mutated AITLs had poor prognosis (p < 0.0001). Genes regulating T-cell receptor (TCR) signaling (CD28, PLCG1, VAV1, FYN) or activation (RHOA <sup>G17V</sup> ) 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<sup>+</sup>PD1<sup>+</sup>) 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 <sup>G17V</sup> , IDH2 <sup>R172</sup> , 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 <sub>FH</sub> and T <sub>CM</sub> (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<sup>+</sup> T-cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.

American Journal of HematologyVol. 100(9)
Oslo University Hospital (NO), Roswell Park Comprehensive Cancer Center (US), City Of Hope National Medical Center (US), University Health Network (CA), Mayo Clinic (US), Memorial Sloan Kettering Cancer Center (US), University of Miami (US), Duke University (US), University of Oslo (NO), University of Toronto (CA), Inha University (KR), Cornell University (US), University of Cambridge (GB), University of Michigan (US), Norwegian Cancer Society (NO), Toronto General Hospital (CA), Dana-Farber Cancer Institute (US), Duke-NUS Medical School (SG), National Cancer Centre Singapore (SG), University of Nebraska Medical Center (US), European Institute of Oncology (IT), University of Naples Federico II (IT), Columbia University (US), University of Bologna (IT), University of Lausanne (CH)
Leukemia and Lymphoma Society, Norges Forskningsråd, National Institutes of Health, National Cancer Institute
No poverty
Openalex Percentile: Top 4%
Lymphoma Diagnosis and Treatment
5.89
DOIOpen Access PDFOpenAlex
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