Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma
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Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma and can be separated into two subtypes based upon molecular features with similarities to germinal centre B-cells (GCB-like) or activated B-cells (ABC-like). Here we identify gain of 3q27.2 as being significantly associated with adverse outcome in DLBCL and linked with the ABC-like subtype. This lesion includes the BCL6 oncogene, but does not alter BCL6 transcript levels or target-gene repression. Separately, we identify expression of BCL6 in a subset of human haematopoietic stem/progenitor cells (HSPCs). We therefore hypothesize that BCL6 may act by 'hit-and-run' oncogenesis. We model this hit-and-run mechanism by transiently expressing Bcl6 within murine HSPCs, and find that it causes mature B-cell lymphomas that lack Bcl6 expression and target-gene repression, are transcriptionally similar to post-GCB cells, and show epigenetic changes that are conserved from HSPCs to mature B-cells. Together, these results suggest that BCL6 may function in a 'hit-and-run' role in lymphomagenesis.
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Sporadic cases in which cancer can be induced in the absence of obvious driver DNA mutations have been reported in mice.
“Although epigenetic perturbations are generally accompanied by mutations in cancer driver genes, sporadic cases in which cancer can be induced in the absence of obvious driver DNA mutations have also been reported in mice 148 .”
From Advances in epigenetics link genetics to the environment and disease (2019) · cites this paper as [148]
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- Authors
- Green, M. R., Vicente-Dueñas, C., Romero-Camarero, I., Long Liu, C., Dai, B., González-Herrero, I., García-Ramírez, I., Alonso-Escudero, E., Iqbal, J., Chan, W. C., Campos-Sanchez, E., Orfao, A., Pintado, B., Flores, T., Blanco, O., Jiménez, R., Martínez-Climent, J. A., Criado, F. J. G., Cenador, M. B. G., Zhao, S., Natkunam, Y., Lossos, I. S., Majeti, R., Melnick, A., Cobaleda, C., Alizadeh, A. A., & Sánchez-García, I.
- Affiliations
- Stanford Medicine (US)
- Consejo Superior de Investigaciones Científicas (ES)
- University of Nebraska Medical Center (US)
- Universidad de Salamanca (ES)
- University of Miami (US)
- Weill Cornell Medicine (US)
- Corresponding author
- Alizadeh, Ash A.
- ORCID
- Venue
- Nature Communications
- Published
- 2014-06-02
- Volume
- 5
- Issue
- 1
- Pages
- 3904-3904
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4321731
- OpenAlex
- W2039255446
- Cited by
- 88
- References
- 75
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 4 · 2022: 4 · 2021: 7 · 2020: 11 · 2019: 13 · 2018: 8 · 2017: 10 · 2016: 10 · 2015: 8 · 2014: 5
- FWCI
- 8.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Nature Communications (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DIGITAL.CSIC (Spanish National Research Council (CSIC)) (submittedVersion)
- Funders
- U.S. Department of Defense
- Damon Runyon Cancer Research Foundation
- Lymphoma Research Foundation
- Chemotherapy Foundation
- Leukemia and Lymphoma Society
- Gabrielle's Angel Foundation for Cancer Research
- Ministerio de Economía y Competitividad (SAF2012-32810, SAF2012, RD06/0020)
- Ministerio de Ciencia e Innovación (CSD2007-0017)
- National Institutes of Health (/ NCI R01, RD06/0020, 2r01ca109335-04a1, R01 CA109335-04A1, CA109335, CA104348)
- Instituto de Salud Carlos III (RD06/0020)
- National Heart, Lung, and Blood Institute (U01HL099995, U01HL099999)
- National Cancer Institute (R01-CA109335, RD06/0020, R01 CA109335-04A1, R01CA104348)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Health Sciences › Medicine › Oncology › Viral-associated cancers and disorders
- Health Sciences › Medicine › Neurology › CNS Lymphoma Diagnosis and Treatment
- Keywords
- BCL6, diffuse large B-cell lymphoma, hematopoietic stem and progenitor cells, germinal center B cells, lymphomagenesis, epigenetic modifications, transient expression
- MeSH terms
- Rituximab, Animals, Antineoplastic Combined Chemotherapy Protocols, B-Lymphocytes, Cyclophosphamide, DNA-Binding Proteins, Doxorubicin, Female, Hematopoietic Stem Cells, Humans, Male, Mice, Transgenic, Phenotype, Prednisone, Prognosis, Vincristine, Gene Expression Regulation, Neoplastic, Lymphoma, Large B-Cell, Diffuse, DNA Methylation, Epigenesis, Genetic, Mice, Proto-Oncogene Proteins c-bcl-6, DNA Copy Number Variations, Antibodies, Monoclonal, Murine-Derived
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