title: BCL6 Antagonizes NOTCH2 to Maintain Survival of Human Follicular Lymphoma Cells.
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 repressesNOTCH2and NOTCH pathway genes. Moreover,BCL6andNOTCH2pathway 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 ofNotch2abrogated 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 inducedNOTCH2expression and suppressed growth of human FL xenograftsin vivoand primary human FL specimensex vivoThese studies suggest that established FLs are thus dependent on BCL6 through its suppression ofNOTCH2Significance: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 ofNOTCH2drives 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Ester
authors.initials: E
authors.lastname: Valls
authors.affiliation: Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, New York.|Institut Gustave Roussy, INSERM U1170, Villejuif and Université Paris Sud, Orsay, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Lobry
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.|Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.|Department of Laboratory Medicine, University of California, San Francisco, San Francisco, California.
authors.forename: Huimin
authors.initials: H
authors.lastname: Geng
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Ling
authors.initials: L
authors.lastname: Wang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Mariano
authors.initials: M
authors.lastname: Cardenas
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Martín
authors.initials: M
authors.lastname: Rivas
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Leandro
authors.initials: L
authors.lastname: Cerchietti
authors.affiliation: Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
authors.forename: Philmo
authors.initials: P
authors.lastname: Oh
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Shao Ning
authors.initials: SN
authors.lastname: Yang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Erin
authors.initials: E
authors.lastname: Oswald
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Camille W
authors.initials: CW
authors.lastname: Graham
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Yanwen
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.|Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hatzi
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.|Division of Hematology/Oncology, Centre for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: Xabier
authors.initials: X
authors.lastname: Agirre
authors.affiliation: Life Sciences Institute, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.|Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Eric
authors.initials: E
authors.lastname: Perkey
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Zhuoning
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: Wayne
authors.initials: W
authors.lastname: Tam
authors.affiliation: Department of Pathology and Perlmutter Cancer Center, New York University School of Medicine, New York, New York.
authors.forename: Kamala
authors.initials: K
authors.lastname: Bhatt
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Weill Cornell Medical College, New York, New York.
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.affiliation: Division of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Zweidler-McKay
authors.affiliation: Life Sciences Institute, Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: Institute for Computational Biomedicine, Weill Cornell Medical College, New York, New York.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: 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.|Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
authors.forename: Weimin
authors.initials: W
authors.lastname: Ci
authors.affiliation: 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.
authors.forename: Iannis
authors.initials: I
authors.lastname: Aifantis
authors.affiliation: 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.
authors.forename: Ari
authors.initials: A
authors.lastname: Melnick
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018858:Germinal Center / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D008224:Lymphoma, Follicular / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D016513:Mice, SCID; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism*; D051883:Receptor, Notch2 / Q000378:metabolism*
chemical_list: C084103:BCL6 protein, human; C497764:NOTCH2 protein, human; D051560:Proto-Oncogene Proteins c-bcl-6; D051883:Receptor, Notch2