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 ZhaoYasodha Natkunam, Izidore S. Lossos, Ravindra Majeti, Ari Melnick, César Cobaleda, Ash A. Alizadeh, Isidro Sánchez-García

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number3904
JournalNature communications
Volume5
DOIs
StatePublished - Jun 2 2014

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B-Cell Lymphoma
Hematopoietic Stem Cells
induction
Cells
stem cells
Stem cells
B-Lymphocytes
Lymphoma, Large B-Cell, Diffuse
genes
Genes
oncogenes
Germinal Center
lesions
set theory
Oncogenes
Epigenomics
Lymphoma
Carcinogenesis
causes
Gene Expression

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Green, M. R., Vicente-Dueñas, C., Romero-Camarero, I., Long Liu, C., Dai, B., González-Herrero, I., ... Sánchez-García, I. (2014). Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nature communications, 5, [3904]. https://doi.org/10.1038/ncomms4904

Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. / Green, Michael R.; Vicente-Dueñas, Carolina; Romero-Camarero, Isabel; Long Liu, Chih; Dai, Bo; González-Herrero, Inés; García-Ramírez, Idoia; Alonso-Escudero, Esther; Iqbal, Javeed; Chan, Wing C.; Campos-Sanchez, Elena; Orfao, Alberto; Pintado, Belén; Flores, Teresa; Blanco, Oscar; Jiménez, Rafael; Martínez-Climent, Jose Angel; Criado, Francisco Javier García; Cenador, María Begoña García; Zhao, Shuchun; Natkunam, Yasodha; Lossos, Izidore S.; Majeti, Ravindra; Melnick, Ari; Cobaleda, César; Alizadeh, Ash A.; Sánchez-García, Isidro.

In: Nature communications, Vol. 5, 3904, 02.06.2014.

Research output: Contribution to journalArticle

Green, MR, Vicente-Dueñas, C, Romero-Camarero, I, Long Liu, C, Dai, B, González-Herrero, I, García-Ramírez, I, Alonso-Escudero, E, Iqbal, J, Chan, WC, Campos-Sanchez, E, Orfao, A, Pintado, B, Flores, T, Blanco, O, Jiménez, R, Martínez-Climent, JA, Criado, FJG, Cenador, MBG, Zhao, S, Natkunam, Y, Lossos, IS, Majeti, R, Melnick, A, Cobaleda, C, Alizadeh, AA & Sánchez-García, I 2014, 'Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma', Nature communications, vol. 5, 3904. https://doi.org/10.1038/ncomms4904
Green MR, Vicente-Dueñas C, Romero-Camarero I, Long Liu C, Dai B, González-Herrero I et al. Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nature communications. 2014 Jun 2;5. 3904. https://doi.org/10.1038/ncomms4904
Green, Michael R. ; Vicente-Dueñas, Carolina ; Romero-Camarero, Isabel ; Long Liu, Chih ; Dai, Bo ; González-Herrero, Inés ; García-Ramírez, Idoia ; Alonso-Escudero, Esther ; Iqbal, Javeed ; Chan, Wing C. ; Campos-Sanchez, Elena ; Orfao, Alberto ; Pintado, Belén ; Flores, Teresa ; Blanco, Oscar ; Jiménez, Rafael ; Martínez-Climent, Jose Angel ; Criado, Francisco Javier García ; Cenador, María Begoña García ; Zhao, Shuchun ; Natkunam, Yasodha ; Lossos, Izidore S. ; Majeti, Ravindra ; Melnick, Ari ; Cobaleda, César ; Alizadeh, Ash A. ; Sánchez-García, Isidro. / Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. In: Nature communications. 2014 ; Vol. 5.
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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.",
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AU - Romero-Camarero, Isabel

AU - Long Liu, Chih

AU - Dai, Bo

AU - González-Herrero, Inés

AU - García-Ramírez, Idoia

AU - Alonso-Escudero, Esther

AU - Iqbal, Javeed

AU - Chan, Wing C.

AU - Campos-Sanchez, Elena

AU - Orfao, Alberto

AU - Pintado, Belén

AU - Flores, Teresa

AU - Blanco, Oscar

AU - Jiménez, Rafael

AU - Martínez-Climent, Jose Angel

AU - Criado, Francisco Javier García

AU - Cenador, María Begoña García

AU - Zhao, Shuchun

AU - Natkunam, Yasodha

AU - Lossos, Izidore S.

AU - Majeti, Ravindra

AU - Melnick, Ari

AU - Cobaleda, César

AU - Alizadeh, Ash A.

AU - Sánchez-García, Isidro

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N2 - 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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