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Nat Commun. 2014 Jun 2;5:3904. doi: 10.1038/ncomms4904.

Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma.

Author information

1
1] Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA [2].
2
1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [3].
3
1] Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n, 37007 Salamanca, Spain [2] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain.
4
Divisions of Oncology and Hematology, Department of Medicine, School of Medicine, Stanford University, Stanford, California 94305, USA.
5
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA.
6
Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, c/Nicolás Cabrera, n° 1, Campus de Cantoblanco, 28049 Madrid, Spain.
7
Servicio de Citometría and Departamento de Medicina, Universidad de Salamanca, 37007 Salamanca, Spain.
8
Genetically Engineered Mouse Facility, CNB-CSIC, 28006 Madrid, Spain.
9
1] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [2] Departamento de Anatomía Patológica, Universidad de Salamanca, 37007 Salamanca, Spain.
10
Departamento de Anatomía Patológica, Universidad de Salamanca, 37007 Salamanca, Spain.
11
1] Institute of Biomedical Research of Salamanca (IBSAL), 37007 Salamanca, Spain [2] Departamento de Fisiología y Farmacología, Universidad de Salamanca, Campus M. Unamuno s/n, 37007 Salamanca, Spain.
12
Division of Oncology, Center for Applied Medical Research (CIMA), University of Navarra, 31008 Pamplona, Spain.
13
Departamento de Cirugía, Universidad de Salamanca, 37007 Salamanca, Spain.
14
Department of Pathology, Stanford University School of Medicine, Stanford, California, 94305 USA.
15
Division of Hematology-Oncology, University of Miami, Sylvester Comprehensive Cancer Center, Miami, Florida 33136, USA.
16
Departments of Medicine and Pharmacology, Weill Cornell Medical College, New York, New York 10021, USA.

Abstract

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.

PMID:
24887457
PMCID:
PMC4321731
DOI:
10.1038/ncomms4904
[Indexed for MEDLINE]
Free PMC Article
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