SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities PMID: 42013317

ADC Targets in Oncology

2026-04-10

SPEN loss drives extra-follicular diffuse large B cell lymphoma with female-specific lethality and therapeutic vulnerabilities

Cancer Discov. 2026 Apr 21:10.1158/2159-8290.CD-25-1458. doi: 10.1158/2159-8290.CD-25-1458.

Benedikt Pelzer ¹ , Cem Meydan ² , Isaac M Spiegel ³ , Ioannis Karagiannidis ² , Min Xia ² , Matt Teater ² , Emma M Welter ⁴ , Zowie E Searcy ⁴ , Laura K Hilton ⁵ , Darko Barisic ³ , Amos Fong ⁶ , Pengyan Fa ³ , Shenon Sethi ⁷ , Irem S Isgor ⁷ , Jessie J Fielding ⁸ , Alireza Karbalayghareh ⁷ , Colin S Burdette ³ , Sravya Tumuluru ² , Sonia M Debek ³ , Sunjae Lee ³ , Ramon Massoni-Badosa ³ , Ceyda Durmaz ⁹ , Eralda Salataj ¹⁰ , Prasath Pararajalingam ¹¹ , Zhengming Chen ¹² , Richard J Pelzl ¹³ , Sanket Shah ³ , Martin A Rivas ¹⁴ , Kenneth B Hoehn ⁸ , Coraline Mlynarczyk ¹⁵ , Hannah M Isles ³ , Xiang Wang ² , Ahmet Dogan ¹⁶ , Kojo S J Elenitoba-Johnson ¹⁶ , David W Scott ¹⁷ , Kostiantyn Dreval ¹⁸ , Ryan D Morin ¹⁹ , Christina S Leslie ¹⁶ , Rishi Puri ²⁰ , Jacob B Geri ⁹ , Christopher R Chin ² , Amy Chadburn ² , Christopher E Mason ² , Hans Christian Reinhardt ²¹ , Montserrat C Anguera ⁴ , Wendy Béguelin ²² , Leandro Venturutti ²³ , Ari M Melnick ²

Affiliations

1. Weill Cornell Medicine New York City United States.
2. Weill Cornell Medicine New York, NY United States.
3. Weill Cornell Medicine New York City, NY United States.
4. University of Pennsylvania Philadelphia, PA United States.
5. BC Cancer Agency Vancouver, BC Canada.
6. British Columbia Cancer Vancouver, British Columbia Canada.
7. Memorial Sloan Kettering Cancer Center New York City, NY United States.
8. Dartmouth College Hanover, NH United States.
9. Weill Cornell Medicine United States.
10. Memorial Sloan Kettering Cancer Center New York, New York United States.
11. Memorial Sloan Kettering Cancer Center New York City, New York United States.
12. Weill Cornell Medicine New York United States.
13. University of Erlangen-Nuremberg Erlangen, Bavaria Germany.
14. University of Miami Miami, FL United States.
15. Yale University New Haven, CT United States.
16. Memorial Sloan Kettering Cancer Center New York, NY United States.
17. British Columbia Cancer Agency Vancouver Canada.
18. BC Cancer Research Centre Vancouver Canada.
19. Simon Fraser University Burnaby, British Columbia Canada.
20. Cornell University Ithaca, NY United States.
21. University Hospital Essen Essen Germany.
22. Weill Cornell Medicine New York, New York United States.
23. University of British Columbia Vancouver, British Columbia Canada.

Abstract

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.