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Cancer Discov. 2017 May;7(5):506-521. doi: 10.1158/2159-8290.CD-16-1189. Epub 2017 Feb 23.

BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.

Author information

1
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
2
Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
3
Institut Gustave Roussy, INSERM U1170, Villejuif and Université Paris Sud, Orsay, France.
4
Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
5
Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
6
Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
8
Division of Hematology/Oncology, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
9
Life Sciences Institute, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
10
Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
11
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
12
Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York. amm2014@med.cornell.edu iannis.aifantis@nyumc.org ciwm@big.ac.cn.
13
Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
14
Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, New York. amm2014@med.cornell.edu iannis.aifantis@nyumc.org ciwm@big.ac.cn.

Abstract

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 NOTCH2 and NOTCH pathway genes. Moreover, BCL6 and NOTCH2 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 Notch2 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 NOTCH2 expression and suppressed growth of human FL xenografts in vivo and primary human FL specimens ex vivo These studies suggest that established FLs are thus dependent on BCL6 through its suppression of NOTCH2Significance: 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 NOTCH2 drives the survival and growth of FL cells as well as GC B cells, which are the FL cell of origin. Cancer Discov; 7(5); 506-21. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 443.

PMID:
28232365
PMCID:
PMC5413414
DOI:
10.1158/2159-8290.CD-16-1189
[Indexed for MEDLINE]
Free PMC Article

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