Lymphomas with combined SpenLOF and Notch2GOF mutations exhibit an AiBC-like phenotype, which is attenuated in males.
Combined SpenLOF and Notch2GOF mutations induce formation of a non-canonical AiBC with MZB features.
Abstract Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCLs derive from follicular B cells engaged in adaptive immune responses. By studying cooccurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extrafollicular trajectory. Using animal models and human specimens, we find that this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory, and a distinct, autoimmune B cell–like state. This trajectory is associated with sex-biased outcomes: Female patients and mice exhibit reduced survival compared with males in our cohorts. Further analysis links this disparity to enhanced X-chromosome–linked expression and functionality of Toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy. Significance: The findings in this article support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.
Highlights from the Science family of journals.
Highlights from the Science family of journals.
Highlights from the Science family of journals.
Sacha Vignieri合作论文数This special issue has been edited by Sacha Vignieri, Andrew M. Sugden, and Elizabeth Pennisi.51
Jake Yeston合作论文数47Di Jiang合作论文数42
Brent M. Grocholski合作论文数Dept Earth Atmospher & Planetary Sci, MIT41Marc S. Lavine合作论文数38Jelena Stajic合作论文数35Yevgeniya Nusinovich合作论文数34
Michael A. Funk合作论文数Dept Chem, MIT29Corinne Simonti合作论文数28Phil Szuromi合作论文数27Caroline Ash合作论文数27Bianca Lopez合作论文数25
A. M. Vanhook合作论文数Science Signaling, AAAS, Washington, DC 20005, USA25Madeleine Seale合作论文数20Mattia Maroso合作论文数20Stella M. Hurtley合作论文数19
Keith T. Smith合作论文数Science.19Sarah H. Ross合作论文数16Catherine A Charneski合作论文数16Courtney S Malo合作论文数16Ian S. Osborne合作论文数16
L. Bryan Ray合作论文数16Melissa Norton合作论文数14Jesse Smith合作论文数14Priscilla N. Kelly合作论文数13Leslie K Ferrarelli合作论文数13Daniela Neuhofer合作论文数12Peter Stern合作论文数12Yury Suleymanov合作论文数11
John F Foley合作论文数Department of Medicine and Department of Microbiology;University of Minnesota;Department of Medicine and Department of Microbiology, University of Minnesota11Seth Thomas Scanlon合作论文数10
Wei Wong合作论文数Science Signaling, American Association for the Advancement of Science10Amy E. Baek合作论文数7Sarah Lemprière合作论文数7Ankit Walia合作论文数6Ekeoma Uzogara合作论文数6Gemma Alderton合作论文数6
Kip Hodges合作论文数School Of Earth and Space Exploration, Arizona State University5Amos Matsiko合作论文数4Michel R Gagné合作论文数4Brandon Berry合作论文数3Laura M. Zahn合作论文数3
Coraline Mlynarczyk合作论文数Department of Medicine and Meyer Cancer Center, Weill Cornell Medicine3Caitlin Czajka合作论文数3
Courtney Malo合作论文数Mayo Clin, Dept Immunol, Rochester, MN 55905 USA3
Amy Chadburn合作论文数Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, Cornell University3
