SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities
Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune responses. By studying co-occurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extra-follicular trajectory. Using animal models and human specimens, we find 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 to 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.
Authors
- Cem Meydan (ORCID: https://orcid.org/0000-0002-0663-6216)
- Sravya Tumuluru (ORCID: https://orcid.org/0009-0001-2091-821X)
- Darko Barišić (ORCID: https://orcid.org/0000-0001-7007-9138)
- Martín A. Rivas (ORCID: https://orcid.org/0000-0002-9603-6897)
- Irem Isgor (ORCID: https://orcid.org/0000-0001-7996-2250)
- Leandro Venturutti (ORCID: https://orcid.org/0000-0002-7264-8370)
- Laura K. Hilton (ORCID: https://orcid.org/0000-0002-6413-6586)
- Pengyan Fa (ORCID: https://orcid.org/0000-0001-7533-007X)
- Benedikt W. Pelzer (ORCID: https://orcid.org/0000-0002-1892-3650)
- Shenon Sethi (ORCID: https://orcid.org/0000-0002-0751-0615)
- Ari Melnick (ORCID: https://orcid.org/0000-0002-8074-2287)
- Kojo S.J. Elenitoba‐Johnson (ORCID: https://orcid.org/0000-0002-1082-1545)
- Ceyda Durmaz
- David W. Scott (ORCID: https://orcid.org/0000-0002-0435-5947)
- Ahmet Doǧan (ORCID: https://orcid.org/0000-0001-6576-5256)
- Xiang Wang (ORCID: https://orcid.org/0000-0003-4603-7186)
- Kenneth B. Hoehn (ORCID: https://orcid.org/0000-0003-0411-4307)
- Prasath Pararajalingam (ORCID: https://orcid.org/0000-0003-3945-3552)
- Matt Teater (ORCID: https://orcid.org/0000-0001-9415-1659)
- Ioannis Karagiannidis (ORCID: https://orcid.org/0000-0001-5850-957X)
- Montserrat C. Anguera (ORCID: https://orcid.org/0000-0003-4992-3079)
- Sonia Dębek (ORCID: https://orcid.org/0000-0001-9267-603X)
- Eralda Salataj (ORCID: https://orcid.org/0000-0001-8661-1686)
- Richard Pelzl
- Alireza Karbalayghareh (ORCID: https://orcid.org/0000-0002-1723-9355)
- Sanket Shah (ORCID: https://orcid.org/0000-0003-3835-9628)
- Coraline Mlynarczyk (ORCID: https://orcid.org/0000-0002-6750-0240)
- Amy Chadburn (ORCID: https://orcid.org/0000-0002-9499-8638)
- Hannah M. Isles (ORCID: https://orcid.org/0000-0002-6019-4842)
- Emma M. Welter
- Ramon Massoni-Badosa (ORCID: https://orcid.org/0000-0001-7115-8145)
- Jacob B. Geri (ORCID: https://orcid.org/0000-0002-9215-5610)
- Christopher R. Chin (ORCID: https://orcid.org/0000-0002-2140-3197)
- Ryan D. Morin (ORCID: https://orcid.org/0000-0003-2932-7800)
- Min Xia (ORCID: https://orcid.org/0000-0002-1093-5008)
- Christina S. Leslie (ORCID: https://orcid.org/0000-0002-4571-5910)
- Christopher E. Mason (ORCID: https://orcid.org/0000-0002-1850-1642)
- Wendy Béguelin (ORCID: https://orcid.org/0000-0002-4894-9229)
- Kostiantyn Dreval (ORCID: https://orcid.org/0000-0002-6214-2843)
- Amos Fong
- Colin Burdette
- Jessie Fielding
- H Christian Reinhardt
- Isaac M. Spiegel (ORCID: https://orcid.org/0000-0002-7326-2090)
- Zhengming Chen (ORCID: https://orcid.org/0000-0001-9437-6452)
- Zowie E. Searcy (ORCID: https://orcid.org/0009-0006-4311-4552)
Institutions
- Dartmouth College (US)
- BC Cancer Agency (CA)
- Memorial Sloan Kettering Cancer Center (US)
- University of British Columbia (CA)
- University of Miami (US)
- Simon Fraser University (CA)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Cornell University (US)
- Yale University (US)
- Essen University Hospital (DE)
- BC Cancer Foundation (CA)
- Canadian Centre for Applied Research in Cancer Control (CA)
- University of Pennsylvania (US)
- Philadelphia University (US)
Publication Details
- Journal
- Cancer Discovery
- Published
- 2026-04-21
- DOI
- https://doi.org/10.1158/2159-8290.cd-25-1458
- Primary Topic
- Lymphoma Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 0.00