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; Isidro Sánchez-García

doi:10.1038/ncomms4904

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

Lymphoma-Myeloma

Research output: Contribution to journal › Article › peer-review

74 Scopus citations

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 language	English (US)
Article number	3904
Journal	Nature Communications
Volume	5
DOIs	https://doi.org/10.1038/ncomms4904
State	Published - Jun 2 2014

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/ncomms4904

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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., ... Sánchez-García, I. (2014). Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma. Nature Communications, 5, Article 3904. https://doi.org/10.1038/ncomms4904

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

@article{a290954a7e3a4f87933e7e32235aa7d0,

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

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.",

author = "Green, {Michael R.} and Carolina Vicente-Due{\~n}as and Isabel Romero-Camarero and {Long Liu}, Chih and Bo Dai and In{\'e}s Gonz{\'a}lez-Herrero and Idoia Garc{\'i}a-Ram{\'i}rez and Esther Alonso-Escudero and Javeed Iqbal and Chan, {Wing C.} and Elena Campos-Sanchez and Alberto Orfao and Bel{\'e}n Pintado and Teresa Flores and Oscar Blanco and Rafael Jim{\'e}nez and Mart{\'i}nez-Climent, {Jose Angel} and Criado, {Francisco Javier Garc{\'i}a} and Cenador, {Mar{\'i}a Bego{\~n}a Garc{\'i}a} and Shuchun Zhao and Yasodha Natkunam and Lossos, {Izidore S.} and Ravindra Majeti and Ari Melnick and C{\'e}sar Cobaleda and Alizadeh, {Ash A.} and Isidro S{\'a}nchez-Garc{\'i}a",

note = "Funding Information: We are grateful to Dr Meinrad Busslinger for continuous and generous help and ideas over the years with this project, Dr Takeshi Tokuhisa for the mouse Bcl6 cDNA, Professor Michael Reth for the mb1-cre mice and Dr E. Dzierzak for the Sca1 promoter Research in A.A.A. group is supported in part by the Damon Runyon Cancer Research Foundation, the Lymphoma Research Foundation, Gabrielle{\textquoteright}s Angel Foundation for Cancer Research, the Leukemia and Lymphoma Society, the National Institutes of Health, and the Department of Defense. Research in I.S.-G. group is supported partially by FEDER and by MICINN (SAF2009-08803 and SAF2012-32810), Junta de Castilla y Le{\'o}n (CSI13A08 and proyecto Biomedicina 2009–2010), MEC OncoBIO Consolider-Ingenio 2010 (ref. no. CSD2007-0017), National Institutes of Health (NIH) grant (R01 CA109335-04A1) and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon. M.R.G. and A.A.A. are Special Fellows of the Leukemia and Lymphoma Society. Funding for single-cell human HSPC studies was provided by NIH grant (U01HL099999) to R.M. and A.A.A. A.M. is supported by NCI R01 CA104348, the Chemotherapy Foundation, the Sam Waxman Cancer Research Foundation, and the G&P Foundation, and is a Leukemia and Lymphoma Society Scholar. Research at C.C.{\textquoteright}s lab is partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI080164), Proyectos Intramurales Especiales (CSIC) and Junta de Castilla y Le{\'o}n (SA060A09 and proyecto Biomedicina 2009–2010). Research of A.O. is supported by a grant from the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain (IISCIII-RTICC RD06/0020/0035-FEDER).",

year = "2014",

month = jun,

day = "2",

doi = "10.1038/ncomms4904",

language = "English (US)",

volume = "5",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - Transient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma

AU - Green, Michael R.

AU - Vicente-Dueñas, Carolina

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

N1 - Funding Information: We are grateful to Dr Meinrad Busslinger for continuous and generous help and ideas over the years with this project, Dr Takeshi Tokuhisa for the mouse Bcl6 cDNA, Professor Michael Reth for the mb1-cre mice and Dr E. Dzierzak for the Sca1 promoter Research in A.A.A. group is supported in part by the Damon Runyon Cancer Research Foundation, the Lymphoma Research Foundation, Gabrielle’s Angel Foundation for Cancer Research, the Leukemia and Lymphoma Society, the National Institutes of Health, and the Department of Defense. Research in I.S.-G. group is supported partially by FEDER and by MICINN (SAF2009-08803 and SAF2012-32810), Junta de Castilla y León (CSI13A08 and proyecto Biomedicina 2009–2010), MEC OncoBIO Consolider-Ingenio 2010 (ref. no. CSD2007-0017), National Institutes of Health (NIH) grant (R01 CA109335-04A1) and by Group of Excellence Grant (GR15) from Junta de Castilla y Leon. M.R.G. and A.A.A. are Special Fellows of the Leukemia and Lymphoma Society. Funding for single-cell human HSPC studies was provided by NIH grant (U01HL099999) to R.M. and A.A.A. A.M. is supported by NCI R01 CA104348, the Chemotherapy Foundation, the Sam Waxman Cancer Research Foundation, and the G&P Foundation, and is a Leukemia and Lymphoma Society Scholar. Research at C.C.’s lab is partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI080164), Proyectos Intramurales Especiales (CSIC) and Junta de Castilla y León (SA060A09 and proyecto Biomedicina 2009–2010). Research of A.O. is supported by a grant from the Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo, Madrid, Spain (IISCIII-RTICC RD06/0020/0035-FEDER).

PY - 2014/6/2

Y1 - 2014/6/2

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.

AB - 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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VL - 5

JO - Nature Communications

JF - Nature Communications

M1 - 3904

ER -

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

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