TitleBCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.
Publication TypeJournal Article
Year of Publication2017
AuthorsValls, 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, and Melnick Ari
JournalCancer Discov
Date Published2017 May
KeywordsAnimals, B-Lymphocytes, Gene Expression Regulation, Neoplastic, Germinal Center, Heterografts, Humans, Lymphoma, Follicular, Mice, Mice, SCID, Proto-Oncogene Proteins c-bcl-6, Receptor, Notch2

<p>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. .</p>

Alternate JournalCancer Discov
PubMed ID28232365
PubMed Central IDPMC5413414
Grant ListR01 CA173636 / CA / NCI NIH HHS / United States
P30 CA016087 / CA / NCI NIH HHS / United States
R01 CA133379 / CA / NCI NIH HHS / United States
R01 CA194923 / CA / NCI NIH HHS / United States
R01 AI091627 / AI / NIAID NIH HHS / United States
R01 CA216421 / CA / NCI NIH HHS / United States
R01 CA149655 / CA / NCI NIH HHS / United States
R01 CA194547 / CA / NCI NIH HHS / United States
T32 GM007863 / GM / NIGMS NIH HHS / United States
R01 CA202025 / CA / NCI NIH HHS / United States
R01 CA169784 / CA / NCI NIH HHS / United States