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Deciphering Pseudoendocrine Sarcoma: a clinicopathological, molecular and epigenetic study suggesting biological links with Solid Pseudopapillary Neoplasm of the Pancreas

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Modern Pathology 2025年

作者： Juan Fernández-Pérez Isabelle Pommepuy Michael Michal Michal Michal Arjen H.G. Cleven Corinne Bouvier Anne Gomez-Brouchet Noelle Weingertner David J. Papke Vickie Y. Jo Jeremy Garcia Abbas Agaimy Rihab Azmani Aurelien Bourdon Isabelle Hostein Isabelle Soubeyran Melissa Alame Valérie Velasco Jean-Michel Coindre François Le Loarer Raul Perret Department of Pathology University Hospital Virgen de la Arrixaca Murcia Spain Department of Pathology Limoges University Hospital Limoges France Department of Pathology Faculty of Medicine in Plzen Charles University Pilsen Czech Republic Bioptical Laboratory Ltd. Plzen Czech Republic Department of Pathology and Medical Biology University Medical Center Groningen University of Groningen Groningen the Netherlands Department of Pathology Amsterdam University Medical Centers Amsterdam the Netherlands Department of Pathology La Timone University Hospital Marseille France Department of Pathology Toulouse University Hospital Toulouse France Department of Pathology Strasbourg University Hospital Strasbourg France Department of Pathology Brigham and Women's Hospital and Harvard Medical School Boston MA Institute of Pathology University Hospital Erlangen Germany Bioinformatics Data and Digital Health Department Institut Bergonié Comprehensive Cancer Center Bordeaux France Department of Biopathology Institut Bergonié Comprehensive Cancer Center F-33000 Bordeaux France University of Bordeaux Talence France INSERM U1218 ACTION Institut Bergonié Bordeaux France

Pseudoendocrine sarcoma (PS) is a recently described neoplasm of uncertain differentiation, characterized by recurrent CTNNB1 mutations, frequent paravertebral location, and a neuroendocrine-like histomorphology. In this study, we report the clinicopathologic, immunohistochemical, transcriptomic and epigenetic findings of twelve PS cases. The tumors affected seven males and five females with a median age of 66 years and were located in the paraspinal/paravertebral region (n=11) and the thigh (n=1). Median tumor size was 82 mm (range: 32-170 mm). Histologically, the tumors comprised sheets and nests of epithelioid to ovoid cells with uniform nuclei and speckled chromatin, frequently associated with extracellular hyaline globules and fibrovascular cords/septa. Uncommon findings included microcalcifications, myxoid stroma, pseudopapillary, pseudoglandular, microcystic, or corded architecture, and lumen and rosette-like structures. Necrosis was absent, and mitotic activity was low. On immunohistochemistry, the tumors showed aberrant nuclear staining for beta-catenin (8/8) and expression of CD56 (7/7), S100 (8/8), Desmin (2/6) and Androgen receptor (1/4). Pan-keratin (AE1/AE3), Progesterone receptor, Synaptophysin, Chromogranin and INSM1 were negative. All tested cases harbored CTNNB1 mutations. Using a customized cohort, methylation profiling revealed that PS formed a common cluster with Solid pseudopapillary neoplasm of the pancreas (SPNP), distinct from all methylation classes from the Heidelberg Sarcoma classifier and a subset of paragangliomas. Transcriptomic analysis showed that PS formed an independent cluster from a control group of tumors (including SPNP). Differential gene expression analysis showed enrichment in genes of the Wnt signaling pathway (HALLMARK gene sets) and biological processes related to sensory perception, among others (GO-BP). Additionally, upregulated genes were related to various fetal cell types from the cell type signature dataset (MSigDB)

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BIOM-39. ESTABLISHMENT OF A CONNECTIVITY SIGNATURE FOR GLIOMAS

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Neuro-Oncology 2020年第SUPPLEMENT_2期22卷 ii10-ii10页

作者： Kessler, Tobias Hai, Ling Hoffmann, Dirk Xie, Ruifan Mandelbaum, Henriette Jung, Erik Schlesner, Matthias Winkler, Frank Wick, Wolfgang Neurology Clinic and National Center for Tumor Diseases University Hospital Heidelberg Heidelberg Germany Bioinformatics and Omics Data Analytics German Cancer Research Center Heidelberg Germany CCU Neurooncology German Cancer Research Center Heidelberg Germany University of Heidelberg and DKFZ Heidelberg Germany

Recent studies have demonstrated extensive cell-to-cell connectivity between tumor cells of gliomas with considerable relevance for tumor progression and therapy resistance. Tumor microtubes (TMs) are neurite-like tumor cell extensions that build these tumor cell networks. Measuring the extent of connectivity in individual tumors has been challenging and depended on anatomical parameters that are difficult to evaluate in patient samples. We performed bulk and single-cell (sc)RNA sequencing of connected vs. unconnected tumor cells from patient-derived xenograft tumors using a newly developed technology that exploits SR101 dye transfer within tumor cell networks. scRNA sequencing was performed with 17 human glioblastoma tumor samples. Three diffuse glioma cohorts from The Cancer Genome Atlas (n = 648), the Chinese Glioma Genome Atlas (n = 668) and the NCT Neuro Master Match (n = 38, IDH-wildtype only) were used to assess clinical properties. A connectivity signature both from bulk and scRNA sequencing data of xenografted primary glioblastoma tumor cells was established. Comparative analysis showed better performance and higher biological relevance of the single-cell derived signature that involves 71 genes. Most of the genes are related to neurogenesis and neural tube development, including several previously recognized TM-relevant genes. Highest connectivity was observed in astrocytic-like and mesenchymal-like tumor cells. Induction of connectivityin vitrowas accompanied with increase of the connectivity signature. The connectivity signature was higher in astrocytic as compared to oligodendrocytic gliomas, and highest in IDH-wildtype gliomas. In accordance, connectivity correlated strongly with dismal survival in all three glioma cohorts. The connectivity signature established here is biologically plausible and associates with prognostically relevant glioma subtypes. It provides the first proof-of-principle that tumor cell connectivity is relevant for the clinical co

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Analysis of Acoustic Features in Gender Identification Model for English and Bahasa Indonesia Telephone Speeches

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Procedia Computer Science 2019年 157卷 199-204页

作者： Muhamad Fitra Kacamarga Tjeng Wawan Cenggoro Arif Budiarto Reza Rahutomo Bens Pardamean Eureka.ai Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia 11480 Bioinformatics and Data Science Research Center Bina Nusantara University Jakarta Indonesia 11480 Computer Science Department BINUS Graduate Program - Master of Computer Science Program Bina Nusantara University Jakarta Indonesia 11480

One of the most interesting topics in auditory problem is determining gender of the speaker. In recent years, machine learning has gained significant attentions as a way to build a classifier from labeled data which also can be implemented to build a gender classifier. In this study we develop gender classifier using two different datasets with different languages, English and Bahasa Indonesia. Each data from both datasets is represented by 20 acoustic features. Multi Layer Perceptron (MLP) is used to build the classification model using all these features and trained only on English dataset. This model is evaluated in both dataset to get the performance matrices consist of accuracy, AUROC, precision and recall. Ultimately, using this model we also identify and compare important features from both dataset to see the different characteristics of English and Bahasa Indonesia speeches.

关键词： Gender Identification Acoustic Feature Speech Recognition

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The evolutionary history of 2,658 cancers (vol 578, pg 122, 2020)

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NATURE 2023年第7948期614卷 E42-E42页

作者： Gerstung, Moritz Jolly, Clemency Leshchiner, Ignaty Dentro, Stefan C. Gonzalez, Santiago Rosebrock, Daniel Mitchell, Thomas J. Rubanova, Yulia Anur, Pavana Yu, Kaixian Tarabichi, Maxime Deshwar, Amit Wintersinger, Jeff Kleinheinz, Kortine Vazquez-Garcia, Ignacio Haase, Kerstin Jerman, Lara Sengupta, Subhajit Macintyre, Geoff Malikic, Salem Donmez, Nilgun Livitz, Dimitri G. Cmero, Marek Demeulemeester, Jonas Schumacher, Steven Fan, Yu Yao, Xiaotong Lee, Juhee Schlesner, Matthias Boutros, Paul C. Bowtell, David D. Zhu, Hongtu Getz, Gad Imielinski, Marcin Beroukhim, Rameen Sahinalp, S. Cenk Ji, Yuan Peifer, Martin Markowetz, Florian Mustonen, Ville Yuan, Ke Wang, Wenyi Morris, Quaid D. Spellman, Paul T. Wedge, David C. Van Loo, Peter European Molecular Biology Laboratory European Bioinformatics Institute (EMBL-EBI) Cambridge UK European Molecular Biology Laboratory Genome Biology Unit Heidelberg Germany Wellcome Sanger Institute Cambridge UK Genome Biology Unit European Molecular Biology Laboratory (EMBL) Heidelberg Germany University of Ljubljana Ljubljana Slovenia The Francis Crick Institute London UK Big Data Institute University of Oxford Oxford UK Wellcome Sanger Institute Wellcome Genome Campus Hinxton UK Big Data Institute Li Ka Shing Centre University of Oxford Oxford UK University of Cambridge Cambridge UK Cambridge University Hospitals NHS Foundation Trust Cambridge UK Department of Applied Mathematics and Theoretical Physics Centre for Mathematical Sciences University of Cambridge Cambridge UK Department of Epidemiology and Biostatistics Memorial Sloan Kettering Cancer Center New York NY USA Department of Statistics Columbia University New York NY USA Department of Haematology University of Cambridge Cambridge UK University of Leuven Leuven Belgium Broad Institute of MIT and Harvard Cambridge MA USA Center for Cancer Research Massachusetts General Hospital Charlestown MA USA Department of Pathology Massachusetts General Hospital Boston MA USA Harvard Medical School Boston MA USA Center for Cancer Research Massachusetts General Hospital Boston MA USA Dana-Farber Cancer Institute Boston MA USA Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA Department of Cancer Biology Dana-Farber Cancer Institute Boston MA USA Oxford NIHR Biomedical Research Centre Oxford UK Oxford NIHR Biomedical Research Centre University of Oxford Oxford UK University of Toronto Toronto Ontario Canada Vector Institute Toronto Ontario Canada Vector Institute Toronto ON Canada Department of Computer Science University of Toronto Toronto ON Canada Ontario Institute for Cancer Research Toronto Ontario Canada University of California Los Angeles

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Correction: LCE: an open web portal to explore gene expression and clinical associations in lung cancer

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Oncogene 2020年第3期39卷 718-719页

作者： Ling Cai ShinYi Lin Luc Girard Yunyun Zhou Lin Yang Bo Ci Qinbo Zhou Danni Luo Bo Yao Hao Tang Jeffrey Allen Kenneth Huffman Adi Gazdar John Heymach Ignacio Wistuba Guanghua Xiao John Minna Yang Xie Quantitative Biomedical Research Center Department of Clinical Sciences UT Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Children's Medical Center Research Institute UT Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Bioinformatics Core Facility UT Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Hamon Center for Therapeutic Oncology Research University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Department of Data Science University of Mississippi Medical Center 2500N State St Jackson MS 39216 USA. Department of Pathology National Cancer Center/Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College 100021 Beijing China. Department of Pathology University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Department of Thoracic/Head and Neck Medical Oncology University of Texas MD Anderson Cancer Center Houston TX 77005 USA. Department of Translational Molecular Pathology University of Texas MD Anderson Cancer Center Houston TX 77030 USA. Quantitative Biomedical Research Center Department of Clinical Sciences UT Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Guanghua.Xiao@UTSouthwestern.edu. Bioinformatics Core Facility UT Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Guanghua.Xiao@UTSouthwestern.edu. Simmons Cancer Center University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. Guanghua.Xiao@UTSouthwestern.edu. Hamon Center for Therapeutic Oncology Research University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. John.Minna@UTSouthwestern.edu. Simmons Cancer Center University of Texas Southwestern Medical Center 5323 Harry Hines Blvd Dallas TX 75390 USA. John.Minna@UTSouthwestern.edu. Department of Pharmacology University of Texas Southwestern Medical C

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

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DNAku Consumers Profile: One of The First Direct to Customer Genetics Testing in Indonesia

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IOP Conference Series: Earth and Environmental Science 2021年第1期794卷

作者： Deby Erina Parung Kians Azizatikarna Dian Amirulloh Erlin Listiyaningsih Bharuno Mahesworo Arif Budiarto Simon Bens Pardamean Genetics Indonesia Jakarta Indonesia 12940 Bioinformatics & Data Science Research Center Bina Nusantara University Jakarta Indonesia 11480 Computer Science Department School of Computer Science Bina Nusantara University Jakarta Indonesia 11480 Computer Science Department BINUS Graduate Program - Master of Computer Science Program Bina Nusantara University Jakarta Indonesia 11480

DNAku test is one of the first direct to customer genetics testing in Indonesia. DNAku test came with a different approach as it gave their customer reports of their genetic predisposition to corresponding traits. Four months after launch, we create consumer report of this genetics testing based on DNAku questionnaire results. We applied three statistical methods, including descriptive statistics, multivariate normality test, and t-test to the demographic data of the DNAku customers. The result shows population clusters which may represent population groups that are interested in genetics testing. The questionnaire also has questions about the customer's lifestyle. The results of these questions were processed to find the lifestyle of DNAku customers.

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A structural haplotype in the 17q21.31 MAPT region is associated with increased risk for chronic traumatic encephalopathy endophenotypes

Cell Reports Medicine

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Cell Reports Medicine 2025年第5期6卷 102084-102084页

作者： Han, Xudong Zhang, Yichi Petrosky, Jillian N. Bald, Sarah Sherva, Richard M. Labadorf, Adam Cherry, Jonathan D. Chung, Jaeyoon Farrell, Kurt Abdolmohammadi, Bobak Durape, Shruti Martin, Brett M. Palmisano, Joseph N. Farrell, John J. Alvarez, Victor E. Huber, Bertrand R. Dwyer, Brigid Daneshvar, Daniel H. Jun, Gyungah R. Lunetta, Kathryn L. Goldstein, Lee E. Katz, Douglas I. Cantu, Robert C. Shenton, Martha E. Cummings, Jeffrey L. Reiman, Eric M. Stern, Robert A. Alosco, Michael L. Tripodis, Yorghos Farrer, Lindsay A. Stein, Thor D. Crary, John F. McKee, Ann C. Mez, Jesse Bioinformatics Graduate Program Boston University Boston MA United States Section of Biomedical Genetics Department of Medicine Boston University Chobanian & Avedisian School of Medicine Boston MA United States Department of Neurology Boston University Chobanian & Avedisian School of Medicine Boston MA United States Boston University Alzheimer's Disease Research Center Boston University Chobanian & Avedisian School of Medicine Boston MA United States Boston VA Healthcare System Boston MA United States Boston University Chronic Traumatic Encephalopathy Center Boston University Boston MA United States Department of Pathology and Laboratory Medicine Boston University Chobanian & Avedisian School of Medicine Boston MA United States Departments of Pathology Neuroscience and Artificial Intelligence & Human Health Neuropathology Brain Bank & Research CoRE Friedman Brain Institute Ronald M. Loeb Center for Alzheimer's Disease Icahn School of Medicine at Mount Sinai New York NY United States Biostatistics and Epidemiology Data Analytics Center Boston University School of Public Health Boston MA United States Bedford VA Healthcare System Bedford MA United States Braintree Rehabilitation Hospital Braintree MA United States Department of Physical Medicine and Rehabilitation Harvard Medical School Boston MA United States Department of Rehabilitation and Human Performance Brain Injury Research Center Icahn School of Medicine at Mount Sinai New York NY United States Department of Neurology Icahn School of Medicine at Mount Sinai New York NY United States Department of Biostatistics Boston University School of Public Health Boston MA United States Department of Ophthalmology Boston University Chobanian & Avedisian School of Medicine Boston MA United States Departments of Biomedical Electrical & Computer Engineering Boston University College of Engineering Boston MA United States Departments of Radiology and Psychiatry Boston University Chobanian & Avedisia

Chronic traumatic encephalopathy (CTE) is a neurodegenerative tauopathy associated with repetitive head impact (RHI) exposure. Genetic variation in the 17q21.31 region, containing microtubule-associated protein tau (MAPT), has been implicated in tauopathies but has not been investigated in CTE. The region includes a megabase-long inversion (H1/H2) and copy-number variations, including α, β, and γ segments, which can be characterized as nine segregating structural haplotypes. We leveraged array SNP data and a reference panel across the 17q21.31 region to impute structural haplotypes and test their association with CTE endophenotypes in 447 European ancestry brain donors with RHI exposure. The H1β1γ1 haplotype was significantly associated with dementia and semi-quantitative tau burden in multiple cortical and medial temporal regions commonly affected in CTE. H1β1γ1 differential expression analyses in dorsolateral frontal cortex implicated cis-acting genes and inflammatory pathways. Taken together, the H1β1γ1 haplotype may help explain CTE heterogeneity among those with similar RHI exposure. © 2025 The Authors

关键词： 17q21.31 chronic traumatic encephalopathy dementia differential gene expression immune system MAPT repetitive head impacts structural haplotypes tauopathy traumatic brain injury

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216P Long-term outcomes of a multicenter phase II trial evaluating the efficacy of preoperative lenvatinib therapy for patients with advanced hepatocellular carcinoma

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Annals of Oncology 2024年 35卷 S1487-S1487页

作者： A. Ichida J. Arita M. Tada E. Hatano S. Eguchi A. Saiura H. Nagano J. Shindoh M. Hashimoto N. Takemura K. Taura Y. Sakamoto Y. Takahashi Y. Seyama Y. Sasaki K. Uemura N. Kokudo K. Hasegawa Hepato-Biliary-Pancreatic Surgery Division Department of Surgery The University of Tokyo Graduate School of Medicine Bunkyo-ku Japan Department of Gastroenterological Surgery Akita University Graduate School of Medicine Akita Japan Department of Gastroenterological Surgery Hyogo Medical University Nishinomiya Japan Department of Surgery Kyoto University Graduate School of Medicine Kyoto Japan Department of Surgery Nagasaki University Graduate School of Biomedical Sciences Nagasaki Japan Department of Hepatobiliary-Pancreatic Surgery Juntendo University School of Medicine Bunkyo-ku Japan Department of Gastroenterological Breast and Endocrine Surgery Yamaguchi University Graduate School of Medicine Ube Japan Hepatobiliary-Pancreatic Surgery Division Department of Gastroenterological Surgery Toranomon Hospital Minato-ku Japan Hepato-Biliary-Pancreatic Surgery Division Department of Surgery NCGM - National Center for Global Health and Medicine Shinjuku-ku Japan Department of Hepato-Biliary-Pancreatic Surgery Kyorin University Hospital Mitaka Japan Division of Hepatobiliary and Pancreatic Surgery The Cancer Institute Hospital of JFCR Koto-ku Japan Department of Hepato-Biliary-Pancreatic Surgery Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Bunkyo-ku Japan Center for Clinical Sciences Clinical Data Management Section NCGM - Center Hospital of the National Center for Global Health and Medicine Shinjuku-ku Japan Biostatistics and Bioinformatics Course The University of Tokyo Bunkyo-ku Japan

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GREGoR: Accelerating Genomics for Rare Diseases

arXiv

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arXiv 2024年

作者： Dawood, Moez Heavner, Ben Wheeler, Marsha M. Ungar, Rachel A. LoTempio, Jonathan Wiel, Laurens Berger, Seth Bernstein, Jonathan A. Chong, Jessica X. Délot, Emmanuèle C. Eichler, Evan E. Gibbs, Richard A. Lupski, James R. Shojaie, Ali Talkowski, Michael E. Wagner, Alex H. Wei, Chia-Lin Wellington, Christopher Wheeler, Matthew T. Carvalho, Claudia M.B. Gifford, Casey A. May, Susanne Miller, Danny E. Rehm, Heidi L. Sedlazeck, Fritz J. Vilain, Eric O'Donnell-Luria, Anne Posey, Jennifer E. Chadwick, Lisa H. Bamshad, Michael J. Montgomery, Stephen B. Human Genome Sequencing Center Baylor College of Medicine HoustonTX United States Department of Molecular and Human Genetics Baylor College of Medicine HoustonTX United States Medical Scientist Training Program Baylor College of Medicine HoustonTX United States Department of Biostatistics University of Washington SeattleWA United States Department of Genetics School of Medicine Stanford University StanfordCA United States Department of Pathology School of Medicine Stanford University Stanford CA United States Stanford Center for Biomedical Ethics School of Medicine Stanford University Stanford CA United States Institute for Clinical and Translational Science University of California IrvineCA United States Division of Cardiovascular Medicine School of Medicine Stanford University Stanford CA United States Division of Genetics and Metabolism Children’s National Rare Disease Institute WashingtonDC United States Center for Genetic Medicine Research Children’s National Rare Disease Institute WashingtonDC United States Department of Genomics and Precision Medicine George Washington University WashingtonDC United States Department of Pediatrics School of Medicine Stanford University Stanford CA United States Department of Pediatrics Dvision of Genetic Medicine University of Washington SeattleWA United States Brotman Baty Institute for Precision Medicine University of Washington SeattleWA United States Department of Genome Sciences University of Washington SeattleWA United States Howard Hughes Medical Institute University of Washington SeattleWA United States Department of Pediatrics Baylor College of Medicine HoustonTX United States Center for Genomic Medicine Massachusetts General Hospital BostonMA United States Program in Medical and Population Genetics Broad Institute of MIT and Harvard BostonMA United States Department of Neurology Massachusetts General Hospital Harvard Medical School BostonMA United States Stanley Center for

Rare diseases are collectively common, affecting approximately one in twenty individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in DNA sequencing, development of new computational and experimental approaches to prioritize genes and genetic variants, and increased global exchange of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize, and evaluate emerging genomics technologies and analytics to accelerate their adoption in clinical practice. Further, all data generated, currently representing ~7500 individuals from ~3000 families, is rapidly made available to researchers worldwide via the Genomic data Science Analysis, Visualization, and Informatics Lab-space (AnVIL) to catalyze global efforts to develop approaches for genetic diagnoses in rare diseases (https://***/data). The majority of these families have undergone prior clinical genetic testing but remained unsolved, with most being exome-negative. Here, we describe the collaborative research framework, datasets, and discoveries comprising GREGoR that will provide foundational resources and substrates for the future of rare disease genomics. © 2024, CC BY.

关键词： Genome

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A phase I/II trial of WT1-specific TCR gene therapy for patients with acute myeloid leukemia and active disease post-allogeneic hematopoietic cell transplantation: skewing towards NK-like phenotype impairs T cell function and persistence

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Nature communications 2025年第1期16卷 5214页

作者： Francesco Mazziotta Lauren E Martin Daniel N Egan Merav Bar Sinéad Kinsella Kelly G Paulson Valentin Voillet Miranda C Lahman Daniel Hunter Thomas M Schmitt Natalie Duerkopp Cecilia C S Yeung Tzu-Hao Tang Raphael Gottardo Yuta Asano Elise C Wilcox Bo Lee Tianzi Zhang Paolo Lopedote Livius Penter Catherine J Wu Filippo Milano Philip D Greenberg Aude G Chapuis Program in Immunology Fred Hutchinson Cancer Center Seattle WA USA. Translational Sciences and Therapeutics Division Fred Hutchinson Cancer Center Seattle WA USA. Immunotherapy Integrated Research Center Fred Hutch Cancer Center Seattle WA USA. Division of Medical Oncology University of Washington Seattle WA USA. Providence-Swedish Cancer Institute Seattle WA USA. Bristol Myers Squibb Boudry Switzerland. Vaccine and Infectious Disease Division Fred Hutchinson Cancer Center Seattle WA USA. Cape Town HVTN Immunology Laboratory Hutchinson Centre Research Institute of South Africa Cape Town South Africa. University of Washington Dept. of Laboratory Medicine and Pathology Seattle WA USA. Biomedical Data Science Center Lausanne University Hospital Lausanne Switzerland. University of Lausanne Lausanne Switzerland. Agora Translational Research Center Lausanne Switzerland. Swiss Institute of Bioinformatics Lausanne Switzerland. Department of Medicine St. Elizabeth's Medical Center Boston University Boston MA USA. Department of Medical Oncology Dana-Farber Cancer Institute Boston MA USA. Department of Hematology Oncology and Tumorimmunology Campus Virchow Klinikum Charité - Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin Berlin Germany. Berlin Institute of Health at Charité-Universitätsmedizin Berlin BIH Biomedical Innovation Academy BIH Charité Digital Clinician Scientist Program Berlin Germany. Departments of Immunology and Medicine University of Washington Seattle WA USA. Program in Immunology Fred Hutchinson Cancer Center Seattle WA USA. achapuis@***. Translational Sciences and Therapeutics Division Fred Hutchinson Cancer Center Seattle WA USA. achapuis@***. Immunotherapy Integrated Research Center Fred Hutch Cancer Center Seattle WA USA. achapuis@***. Division of Medical Oncology University of Washington Seattle WA USA. achapuis@fredhutch.org.

Relapsed and/or refractory acute myeloid leukemia (AML) post-allogeneic hematopoietic cell transplantation (HCT) is usually fatal. We previously reported that post-HCT immunotherapy with Epstein-Barr virus (EBV)-specific donor CD8 T cells engineered to express a Wilms Tumor Antigen 1-specific T-cell receptor (T) appeared to prevent relapse in high-risk patients. In this phase I/II clinical trial (NCT01640301), we evaluated safety (primary endpoint), persistence and efficacy (secondary endpoints) of EBV- or Cytomegalovirus (CMV)-specific T in fifteen patients with active AML post-HCT. Infusions were well tolerated, with no dose-limiting toxicities or serious adverse events related to the product. However, T cells did not clearly improve outcomes despite EBV-specific T cells showing enhanced potential for prolonged persistence compared to CMV-specific T. Investigating the fate of persisting T, we identified a shift towards natural killer-like (NKL) terminal differentiation, distinct from solid tumor-associated canonical exhaustion programs. In one patient, treatment with azacitidine appeared to mitigate this NKL skewing, promoting T persistence. These findings suggest that AML drives a distinct form of T-cell dysfunction, highlight the need for targeted approaches that preserve T-cell fitness, ultimately improving the efficacy of cellular therapies for AML.

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