Journal article
Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma
Blood cancer journal (New York), Vol.15(1), 120
07/12/2025
DOI: 10.1038/s41408-025-01326-5
PMCID: PMC12255755
PMID: 40651974
Abstract
Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not experience a durable response to frontline immunochemotherapy, and prospective identification of high-risk cases that may benefit from personalized therapeutic management remains an unmet need. Molecular phenotyping techniques have established a landscape of genomic variants in diagnostic DLBCL; however, these have not yet been applied in large-scale studies of relapsed/refractory DLBCL, resulting in incomplete characterization of mechanisms driving tumor progression and treatment resistance. Here, we performed an integrated multiomic analysis on 228 relapsed/refractory DLBCL samples, including 24 with serial biopsies. Refined cell-of-origin subtyping identified patients harboring GCB and DZsig+ relapsed/refractory tumors in cases with primary refractory disease with remarkably poor outcomes, and comparative analysis of genomic features between relapsed and diagnostic samples identified subtype-specific mechanisms of therapeutic resistance driven by frequent alteration to MYC, BCL2, BCL6, and TP53 among additional strong lymphoma driver genes. Tumor evolution dynamics suggest innate mechanisms of chemoresistance are present in many DLBCL tumors at diagnosis, and that relapsed/refractory tumors are primarily comprised of a homogenous clonal expansion with reduced tumor microenvironment activity. Adaptation of personalized therapeutic strategies targeting DLBCL subtype-specific resistance mechanisms should be considered to benefit these high-risk populations.
Details
- Title: Subtitle
- Integrated genomics with refined cell-of-origin subtyping distinguishes subtype-specific mechanisms of treatment resistance and relapse in diffuse large B-cell lymphoma
- Creators
- Janek S Walker - Mayo Clinic in ArizonaKerstin Wenzl - Mayo Clinic in ArizonaJoseph P Novak - Mayo Clinic in ArizonaMatthew E Stokes - Bristol-Myers SquibbMelissa A Hopper - Mayo Clinic in ArizonaAbigail R Dropik - Mayo Clinic in ArizonaMiranda S Siminski - Mayo Clinic in ArizonaAllison M Bock - Mayo Clinic in ArizonaVivekananda Sarangi - Mayo Clinic in FloridaMaria Ortiz - Informatics and Predictive Sciences, Celgene Institute for Translational Research Europe (CITRE), Seville, SpainNicholas Stong - Bristol-Myers SquibbC Chris Huang - Bristol-Myers SquibbMatthew J Maurer - Mayo Clinic in ArizonaBrian K Link - University of IowaStephen M Ansell - Mayo Clinic in ArizonaThomas M Habermann - Mayo Clinic in ArizonaThomas E Witzig - Mayo Clinic in ArizonaRebecca L King - Mayo Clinic in ArizonaGrzegorz Nowakowski - Mayo Clinic in ArizonaJames R Cerhan - Mayo Clinic in FloridaAnita K Gandhi - Bristol-Myers SquibbAnne J Novak - Mayo Clinic in Arizona
- Resource Type
- Journal article
- Publication Details
- Blood cancer journal (New York), Vol.15(1), 120
- DOI
- 10.1038/s41408-025-01326-5
- PMID
- 40651974
- PMCID
- PMC12255755
- NLM abbreviation
- Blood Cancer J
- ISSN
- 2044-5385
- eISSN
- 2044-5385
- Publisher
- SPRINGERNATURE
- Grant note
- U01 CA195568 / NCI NIH HHS SPORE-P50 CA97274 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R01 CA212162-01A1 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) T32AI170478 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 10.53354/ACS.PF-24-1301715-01-CCB.pc.gr.222062 / American Cancer Society (American Cancer Society, Inc.)
- Language
- English
- Date published
- 07/12/2025
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Epidemiology; Internal Medicine
- Record Identifier
- 9984845649202771
Metrics
2 Record Views