An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression

Baochun Zhang; Dinis Pedro Calado; Zhe Wang; Sebastian Fröhler; Karl Köchert; Yu Qian; Sergei B Koralov; Marc Schmidt-Supprian; Yoshiteru Sasaki; Christine Unitt; Scott Rodig; Wei Chen; Riccardo Dalla-Favera; Frederick W Alt; Laura Pasqualucci; Klaus Rajewsky

doi:10.1016/j.celrep.2015.03.059

An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression

Cell Rep. 2015 May 5;11(5):715-26. doi: 10.1016/j.celrep.2015.03.059. Epub 2015 Apr 23.

Authors

Baochun Zhang¹, Dinis Pedro Calado², Zhe Wang³, Sebastian Fröhler⁴, Karl Köchert⁴, Yu Qian⁵, Sergei B Koralov⁶, Marc Schmidt-Supprian⁷, Yoshiteru Sasaki⁸, Christine Unitt⁹, Scott Rodig⁹, Wei Chen⁴, Riccardo Dalla-Favera¹⁰, Frederick W Alt¹¹, Laura Pasqualucci¹⁰, Klaus Rajewsky¹²

Affiliations

¹ Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. Electronic address: [email protected].
² Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany; Cancer Research UK, London Research Institute, London WC2A 3LY, UK; Peter Gorer Department of Immunobiology, Kings College London, London SE1 9RT, UK. Electronic address: [email protected].
³ Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany.
⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁶ Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Pathology, New York University School of Medicine, New York, NY 10016, USA.
⁷ Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Hematology and Oncology, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, Munich 81675, Germany.
⁸ Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁹ Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
¹⁰ Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
¹¹ Howard Hughes Medical Institute, Program in Cellular and Molecular Medicine, Boston Children's Hospital, and Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
¹² Program of Cellular and Molecular Medicine, Children's Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA; Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany. Electronic address: [email protected].

Abstract

Diffuse large B cell lymphoma (DLBCL) is a complex disease comprising diverse subtypes and genetic profiles. Possibly because of the prevalence of genetic alterations activating canonical NF-κB activity, a role for oncogenic lesions that activate the alternative NF-κB pathway in DLBCL has remained elusive. Here, we show that deletion/mutation of TRAF3, a negative regulator of the alternative NF-κB pathway, occurs in ∼15% of DLBCLs and that it often coexists with BCL6 translocation, which prevents terminal B cell differentiation. Accordingly, in a mouse model constitutive activation of the alternative NF-κB pathway cooperates with BCL6 deregulation in DLBCL development. This work demonstrates a key oncogenic role for the alternative NF-κB pathway in DLBCL development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / cytology
B-Lymphocytes / immunology
B-Lymphocytes / metabolism
Cell Differentiation
Cell Line, Tumor
Cell Survival
DNA-Binding Proteins / deficiency
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism*
Gene Expression Regulation, Neoplastic*
Humans
Lymphoma, Large B-Cell, Diffuse / metabolism
Lymphoma, Large B-Cell, Diffuse / pathology
Mice
Mice, Knockout
NF-kappa B / metabolism*
NF-kappaB-Inducing Kinase
Protein Serine-Threonine Kinases / genetics
Protein Serine-Threonine Kinases / metabolism
Proto-Oncogene Proteins c-bcl-6
Signal Transduction
TNF Receptor-Associated Factor 3 / genetics
TNF Receptor-Associated Factor 3 / metabolism

Substances

Bcl6 protein, mouse
DNA-Binding Proteins
NF-kappa B
Proto-Oncogene Proteins c-bcl-6
TNF Receptor-Associated Factor 3
Protein Serine-Threonine Kinases

Abstract

Publication types

MeSH terms

Substances

Grants and funding