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

Michael R. Green, Carolina Vicente-Dueñas, Isabel Romero-Camarero, Chih Long Liu, Bo Dai, Inés González-Herrero, Idoia García-Ramírez, Esther Alonso-Escudero, Javeed Iqbal, Wing C. Chan, Elena Campos-Sanchez, Alberto Orfao, Belén Pintado, Teresa Flores, Oscar Blanco, Rafael Jiménez, Jose Angel Martínez-Climent, Francisco Javier García Criado, María Begoña García Cenador, Shuchun Zhao, Yasodha Natkunam, Izidore S. Lossos, Ravindra Majeti, Ari Melnick, César Cobaleda, Ash A. Alizadeh () and Isidro Sánchez-García ()
Additional contact information
Michael R. Green: School of Medicine, Stanford University
Carolina Vicente-Dueñas: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n
Isabel Romero-Camarero: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n
Chih Long Liu: School of Medicine, Stanford University
Bo Dai: School of Medicine, Stanford University
Inés González-Herrero: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n
Idoia García-Ramírez: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n
Esther Alonso-Escudero: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n
Javeed Iqbal: University of Nebraska Medical Center
Wing C. Chan: University of Nebraska Medical Center
Elena Campos-Sanchez: Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, c/Nicolás Cabrera, n° 1, Campus de Cantoblanco
Alberto Orfao: Universidad de Salamanca
Belén Pintado: Genetically Engineered Mouse Facility, CNB-CSIC
Teresa Flores: Institute of Biomedical Research of Salamanca (IBSAL)
Oscar Blanco: Universidad de Salamanca
Rafael Jiménez: Institute of Biomedical Research of Salamanca (IBSAL)
Jose Angel Martínez-Climent: Center for Applied Medical Research (CIMA), University of Navarra
Francisco Javier García Criado: Universidad de Salamanca
María Begoña García Cenador: Universidad de Salamanca
Shuchun Zhao: Stanford University School of Medicine
Yasodha Natkunam: Stanford University School of Medicine
Izidore S. Lossos: University of Miami, Sylvester Comprehensive Cancer Center
Ravindra Majeti: School of Medicine, Stanford University
Ari Melnick: Weill Cornell Medical College
César Cobaleda: Centro de Biología Molecular Severo Ochoa, CSIC/Universidad Autónoma de Madrid, c/Nicolás Cabrera, n° 1, Campus de Cantoblanco
Ash A. Alizadeh: School of Medicine, Stanford University
Isidro Sánchez-García: Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC/Universidad de Salamanca, Campus M. de Unamuno s/n

Nature Communications, 2014, vol. 5, issue 1, 1-13

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4904

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