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
Affiliations
Baochun Zhang
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Dinis Pedro Calado
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Zhe Wang
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Sebastian Fröhler
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany
Karl Köchert
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany
Yu Qian
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
Sergei B. Koralov
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Marc Schmidt-Supprian
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Yoshiteru Sasaki
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
Christine Unitt
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Scott Rodig
Department of Pathology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Wei Chen
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany
Riccardo Dalla-Favera
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Frederick W. Alt
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
Laura Pasqualucci
Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
Klaus Rajewsky
Program of Cellular and Molecular Medicine, Children’s Hospital, and Immune Disease Institute, Harvard Medical School, Boston, MA 02115, USA
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.
