BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells

Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and repr...

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Published in:Cancer discovery 2017-05, Vol.7 (5), p.506-521
Main Authors: Valls, Ester, Lobry, Camille, Geng, Huimin, Wang, Ling, Cardenas, Mariano, Rivas, Martín, Cerchietti, Leandro, Oh, Philmo, Yang, Shao Ning, Oswald, Erin, Graham, Camille W, Jiang, Yanwen, Hatzi, Katerina, Agirre, Xabier, Perkey, Eric, Li, Zhuoning, Tam, Wayne, Bhatt, Kamala, Leonard, John P, Zweidler-McKay, Patrick A, Maillard, Ivan, Elemento, Olivier, Ci, Weimin, Aifantis, Iannis, Melnick, Ari
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - metabolism
Gene Expression Regulation, Neoplastic - physiology
Germinal Center - metabolism
Heterografts
Humans
Lymphoma, Follicular - metabolism
Lymphoma, Follicular - pathology
Mice
Mice, SCID
Proto-Oncogene Proteins c-bcl-6 - metabolism
Receptor, Notch2 - metabolism
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Summary:Although the BCL6 transcriptional repressor is frequently expressed in human follicular lymphomas (FL), its biological role in this disease remains unknown. Herein, we comprehensively identify the set of gene promoters directly targeted by BCL6 in primary human FLs. We noted that BCL6 binds and represses and NOTCH pathway genes. Moreover, and pathway gene expression is inversely correlated in FL. Notably, BCL6 upregulation is associated with repression of NOTCH2 and its target genes in primary human and murine germinal center (GC) cells. Repression of NOTCH2 is an essential function of BCL6 in FL and GC B cells because inducible expression of abrogated GC formation in mice and killed FL cells. Indeed, BCL6-targeting compounds or gene silencing leads to the induction of NOTCH2 activity and compromises survival of FL cells, whereas NOTCH2 depletion or pathway antagonists rescue FL cells from such effects. Moreover, BCL6 inhibitors induced expression and suppressed growth of human FL xenografts and primary human FL specimens These studies suggest that established FLs are thus dependent on BCL6 through its suppression of We show that human FLs are dependent on BCL6, and primary human FLs can be killed using specific BCL6 inhibitors. Integrative genomics and functional studies of BCL6 in primary FL cells point toward a novel mechanism whereby BCL6 repression of drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. .
ISSN:2159-8274
2159-8290
DOI:10.1158/2159-8290.cd-16-1189