Somatic <i>IRF4</i> mutations and thymic tropism in primary mediastinal large B-cell lymphoma
Abstract
Abstract Disease-defining signatures in lymphomas, driven by intricate molecular mechanisms, have advanced molecular taxonomies, refined classification, and may guide clinical management; however, the role of these signatures in driving disease hallmarks, including subtype-specific organotropism, remains largely unexplored. Primary mediastinal large B-cell lymphoma (PMBCL) is an exemplary lymphoma characterized by disease manifestations in the thymic niche, unique genetic alterations, and immune escape. Here, we identified interferon regulatory factor 4 (IRF4)–C99R mutations uniquely occurring in PMBCL through mutational meta-analysis of large-scale data sets. By integrating multiomics approaches with genome editing in PMBCL cells, we revealed that IRF4-C99R contributes to a differentiation block phenotype. Specifically, we showed that IRF4-C99R reduces its binding to the interferon-stimulated response element (ISRE) motif within PRDM1, encoding a key transcriptional regulator of B-cell differentiation, resulting in decreased PRDM1 expression. Additionally, IRF4-C99R suppresses Traf2 and Nck-interacting kinase, a key interferon gamma (IFN-γ) pathway regulator, by impairing ISRE motif binding, thereby reducing IFN-γ signaling and increasing thymus and activation-regulated chemokine (TARC) expression, which drives TARC-mediated chemotaxis of T regulatory cells. We also revealed that IRF4-C99R upregulates ephrin type-B receptor 1 (EPHB1) through noncanonical activating protein 1–IRF composite motif binding and showed that overexpression of EPHB1 in an immunocompetent syngeneic lymphoma model influenced organotropism to favor thymic localization, without affecting overall tumor burden. IRF4-C99R mutation–induced phenotypes were validated in primary PMBCL tissues using single-nuclei RNA sequencing, confirming that the molecular mechanisms observed in vitro align with the pathophysiology of PMBCL in patients. Together, these findings demonstrate how a single genetic mutation orchestrates the coordinated regulation of hallmark traits including thymus-specific tropism in PMBCL.
Article Details
Authors (32)
Shinya Rai
2British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
Gerben Duns
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Fabian Frontzek
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Jasper C. H. Wong
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Yifan Yin
Michael Yu Li
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Makoto Kishida
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Manabu Fujisawa
2Institute of Medicine, University of Tsukuba, Department of Hematology, Tsukuba, Japan
Shannon Healy
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Elena Viganò
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Aixiang Jiang
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Bruce Woolcock
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Adele Telenius
2British Columbia Cancer, Centre for Lymphoid Cancer, Vancouver, Canada
Susana Ben-Neriah
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Barbara Meissner
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Merrill Boyle
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Hisae Nakamura
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Luke O’Brien
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Claudia Cassidy
1Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
Andrew Lytle
7BC Cancer, Vancouver, Canada
Pedro Farinha
6BC Cancer, Vancouver, BC, Canada
Graham Slack
7BC Cancer, Vancouver, Canada
Laura K. Hilton
4Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada
Ryan D. Morin
4Centre for Lymphoid Cancer, BC Cancer Research Institute, Vancouver, BC, Canada
Leandro Venturutti
2BC Cancer Research Institute, Vancouver, Canada
Tomohiro Aoki
Nicole Wretham
7Department of Experimental Therapeutics, British Columbia Cancer Research Institute, Vancouver, BC, Canada
Jonathan W. Bush
4Department of Pathology and Laboratory Medicine, The University of British Columbia, Vancouver, BC, Canada
Laura Evgin
Kerry J. Savage
6BC Cancer, Vancouver, BC, Canada
David W. Scott
5Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, Canada
Christian Steidl
5Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, Canada