Year: 2026
Type: preprint
Abstract: The thymus provides a specialized niche for lymphocyte differentiation, yet the developmental trajectories of its rare B-cell population and their relationship to thymic B-cell lymphomagenesis remain poorly understood. Here, we integrate single-cell multiomics and spatial profiling across human tissues to delineate a B-cell differentiation program selectively represented in the human thymus. This program links CCL17⁺ and germinal center-like B-cell states along a trajectory distinct from canonical germinal center differentiation and can be recapitulated in vitro by signals operating in the thymic medulla. Extending this framework across human B-cell lymphomas, we identify an inherent malignant cell state in PMBCL that shares transcriptional and epigenetic features with CCL17⁺ thymic B cells. This malignant state associates with early clonal positions in reconstructed B-cell receptor phylogenies and persists within tumor microenvironments distinct from the thymic niche. Together, these findings support a model in which thymus-specific B-cell differentiation programs are redeployed during thymic B-cell lymphomagenesis. Highlights ✓ CCL17⁺ B-cell states are selectively represented in the human thymus ✓ Thymic medullary signals recapitulate CCL17⁺-to-germinal center-like differentiation ✓ Primary mediastinal large B-cell lymphomas harbor a malignant counterpart of CCL17⁺ thymic B cells ✓ The malignant counterpart occupies early nodes in clonal phylogenies
Authors: Shinya Rai, Yifan Yin, Manabu Fujisawa, Makoto Kishida, Michael Yu Li, Jeffrey Niu, Aixiang Jiang, Laura K Hilton, Amos Fong, Gerben Duns, Adèle Telenius, Barbara Meissner, Merrill Boyle, Hisae Nakamura, Alexandra Roos, Shiva Daryani, Luke ÒBrien, Claudia Cassidy, Shaocheng Wu, Eric Lee, Andrew Lytle, Pedro Farinha, Graham Slack, Jonathan W Bush, Ryan D Morin, Leandro Venturutti, Andrew P Weng, Andrew Roth, Brad H Nelson, Kerry J Savage, Tomohiro Aoki, Clementine Sarkozy, David W Scott, Christian Steidl
Institutions: BC Cancer Agency, Kindai University, University of Tsukuba, University of British Columbia, Simon Fraser University, BC Cancer – Victoria, University Health Network, University of Toronto, Princess Margaret Cancer Centre, Université de Versailles Saint-Quentin-en-Yvelines, Imagerie, Radiothérapie Innovante et médecine des Systèmes, Institut Curie
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7223035818