TitleTransient expression of Bcl6 is sufficient for oncogenic function and induction of mature B-cell lymphoma.
Publication TypeJournal Article
Year of Publication2014
AuthorsGreen, Michael R., Vicente-Dueñas Carolina, Romero-Camarero Isabel, Liu Chih Long, 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 Gar, Cenador María Begoña Ga, Zhao Shuchun, Natkunam Yasodha, Lossos Izidore S., Majeti Ravindra, Melnick Ari, Cobaleda Cesar, Alizadeh Ash A., and Sanchez-Garcia Isidro
JournalNat Commun
Volume5
Pagination3904
Date Published2014 Jun 02
ISSN2041-1723
KeywordsAnimals, Antibodies, Monoclonal, Murine-Derived, Antineoplastic Combined Chemotherapy Protocols, B-Lymphocytes, Cyclophosphamide, DNA Copy Number Variations, DNA Methylation, DNA-Binding Proteins, Doxorubicin, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Hematopoietic Stem Cells, Humans, Lymphoma, Large B-Cell, Diffuse, Male, Mice, Mice, Transgenic, Phenotype, Prednisone, Prognosis, Proto-Oncogene Proteins c-bcl-6, Rituximab, Vincristine
Abstract

<p>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. </p>

DOI10.1038/ncomms4904
Alternate JournalNat Commun
PubMed ID24887457
PubMed Central IDPMC4321731
Grant ListU01 HL099995 / HL / NHLBI NIH HHS / United States
U01 HL099999 / HL / NHLBI NIH HHS / United States
R01 CA109335-04A1 / CA / NCI NIH HHS / United States
R01 CA109335 / CA / NCI NIH HHS / United States
U01HL099999 / HL / NHLBI NIH HHS / United States
R01 CA104348 / CA / NCI NIH HHS / United States