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2993 Integrative Genomic and Transcriptomic Analysis Reveals Targetable Vulnerabilities in Angioimmunoblastic T-Cell Lymphoma

Program: Oral and Poster Abstracts
Session: 621. Lymphomas: Translational—Molecular and Genetic: Poster II
Hematology Disease Topics & Pathways:
Lymphomas, T Cell lymphoma, Diseases, Lymphoid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Alyssa Bouska, PhD1*, Weiwei Zhang, Ph.D2*, Sunandini Sharma, MS2*, Harald Holte, MD, PhD3, Ab Rauf Shah, Ph.D2*, Waseem Gul Lone, PhD2*, Luca Vincenzo Cappelli, MD, PhD4*, Danilo Fiore, Ph.D5,6*, Qiang Gong, PhD7*, Tayla Heavican-Foral, PhD2, Jeffrey Cannatella, M.D.2*, Catalina Amador, MD8*, Aiza Arif2*, Lynette Smith, Ph.D9*, Soon Thye Lim, MBBS, MRCP10*, Choon Kiat Ong, Ph.D11*, Andrew L. Feldman, MD12, Ming-Qing Du, MB, PhD, FRCPath13, Laurence de Leval, MD, PhD14, Timothy C. Greiner, MS, MD2*, Kai Fu, MD, PhD15, Gunhild Trøen, PhD16*, Daniel Vodak17*, Sigve Nakken, PhD18*, Jan Delabie, MD, PhD19*, David M. Weinstock, MD20, Stefano A. Pileri, MD, PhD21, Antonella Laginestra, Ph.D22*, Kyeongjin Kim, PhD23*, Utpal Pajvani, MD, PhD24*, Julie M. Vose, MD, MBA25, Dennis D Weisenburger, MD2*, Sandeep Dave, M.D.26*, Giorgio Inghirami, MD27*, Wing C. Chan, MD7 and Javeed Iqbal, PhD, MSc2*

1Department of Pathology and Microbiology, University of Nebraska Medical Center, OMAHA, NE
2Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE
3Department of Oncology, Oslo University Hospital, Oslo, NOR
4Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY
51. Department of Pathology and Laboratory Medicine, Weil Cornell Medical College, New York City, NY
6Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
7Department of Pathology, City of Hope National Medical Center, Duarte, CA
8University of Miami, Miami, FL
9Department of Biostatistics, UNMC, Omaha, NE
10National Cancer Centre, Singapore, Singapore, SGP
11Division of Medical Oncology, National Cancer Centre Singapore / Duke-NUS Medical School, Singapore, Singapore, Singapore
12Department of Laboratory Medicine and Pathology, Division of Hematopathology, Mayo Clinic, Rochester, MN
13Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
14Hôpital Universitaire de Lausanne, Lausanne, Switzerland
15Department of Pathology & Laboratory Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, NY
16Oslo University Hospital, Oslo, Norway
17Oslo University Hospital,, Oslo, Norway
18University of Oslo, Oslo, Norway
19University of Toronto, Toronto, ON, CAN
20Dana Farber Cancer Institute, Boston, MA
21Division of Hematopathology, Istituto Europeo di Oncologia, Milano, Italy
22European Institute of Oncology IRCCS,, Milan, Italy
23Inha University, Incheon, KOR
24Columbia University, New York, NY
25University of Nebraska Medical Center, Omaha, NE
26Duke University Medical Center, Durham, NC
27Weill Cornell Medicine, New York, NY

Follicular helper T-cell lymphoma of the angioimmunoblastic type (AITL) is associated with dismal prognosis. We performed functional genomic approaches including whole-exome sequencing (WES; n=119), transcriptomic (n=78) and methylation (n=40) analysis. We identified recurrent mutations in known epigenetic drivers (TET2, DNMT3A, IDH2R172), and also identified novel ones (TET3, KMT2D). Somatic mutation of all three epigenetic drivers (TET2, IDH2, and DNMT3A) was associated with poor prognosis (p<.001). Mutations in genes regulating T-cell receptor (TCR) signaling (CD28, VAV1,FYN,PLCG1) or activation (RHOAG17V), and regulators of the PI3K pathway (PIK(3)C members, PTEN,PHLPP-1/-2) were also found. Genome-wide DNA-methylation analysis integrated with mRNA expression profiling also revealed epigenetic alterations in genes regulating TCR-RHOA/B/C or PI3K-signaling. TET2 loss was noted in 85% AITLs and was significantly associated with RHOAG17V, CD28 and IDH2R172 mutations. AITLs lacking RHOAG17V tended to have mutations regulating the JAK-STAT pathway (JAK2, JAK3, STAT1,STAT3, SOCS1). RNA-seq analysis identified fusion transcripts in genes regulating TCR activation (8%), revealed a restricted TCR repertoire in the majority of cases (a=87%, b=72%), and showed the presence of Epstein–Barr virus transcriptome (73%). GEP demonstrated association of B-cells in the tumor-milieu with better prognosis (p=.006), while dendritic cells were associated with worse prognosis (p=.001), which was further validated by immunohistochemistry using CD20, CD68, and CD163 antibodies. RNA-seq and corresponding WES analysis of 12 AITL patient-derived-xenografts (PDX) showed that bi-allelic TET2 mutations, DNMT3A mutations or sub-clonal mutations (PLCG1, PHLPP2) were propagated in sequential passages. Gene signatures related to TFH (follicular helper) and TCM (central memory) were also well-maintained in secondary passages in PDX models. Gene signatures of late PDX passages (3rd-5th) were enriched with genes related to proliferation and metabolic reprogramming, and in an independent cohort of AITLs, high expression of T3/T5 related signatures was associated with worse outcome (p=0.02/p=0.009). Low mRNA expression of PHLPP2 predicted poor prognosis (p=.03) and engineered PHLPP2 loss showed enhanced PI(3)K activation and FOXO1 inactivation in CD4+ T-cells in-vitro. Thus, we defined the genomic landscape for AITL, which is largely characterized by epigenetic alterations, TCR signaling and PI3K/AKT dysregulation, which may be amenable for therapeutic targeting.

Disclosures: Holte: Nordic Nanovector: Other: Safety Committee; Pierre Fabre: Other: Advisory Board; Genmab: Other: DMC Committee; Incyte: Other: Advisory Board, Review Committee. de Leval: Lunaphore: Consultancy; Novartis: Consultancy; Bio Ascend: Consultancy; Bayer: Consultancy; Abb Vie: Consultancy. Pileri: CELGENE: Other: Advisory board; ROCHE: Speakers Bureau; NANOSTRING: Other: Advisory Board; Stemline: Speakers Bureau; Diatech Pharmacogenetics: Consultancy; Beigene: Research Funding, Speakers Bureau; Eli Lilly: Speakers Bureau. Vose: Eli Lilly and Company; Epizyme, Kite, Loxo, Novartis: Research Funding; AbbVie, MEI Pharma: Consultancy. Dave: Data Driven Bioscience: Current equity holder in private company.

*signifies non-member of ASH