An oncogenic role for alternative NF-κB signaling in DLBCL revealed upon deregulated BCL6 expression.
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.
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: baochun_zhang@dfci.harvard.edu.
Baochun
B
Zhang
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: dinis.calado@cancer.org.uk.
Dinis Pedro
DP
Calado
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.
Zhe
Z
Wang
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany.
Sebastian
S
Fröhler
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany.
Karl
K
Köchert
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
Yu
Y
Qian
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.
Sergei B
SB
Koralov
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.
Marc
M
Schmidt-Supprian
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.
Yoshiteru
Y
Sasaki
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Christine
C
Unitt
Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.
Scott
S
Rodig
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Str 10, Berlin 13125, Germany.
Wei
W
Chen
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.
Riccardo
R
Dalla-Favera
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.
Frederick W
FW
Alt
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.
Laura
L
Pasqualucci
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: klaus.rajewsky@mdc-berlin.de.
Klaus
K
Rajewsky
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6; D015398:Signal Transduction; D048008:TNF Receptor-Associated Factor 3 / Q000235:genetics / Q000378:metabolism; D000097782:NF-kappaB-Inducing Kinase
D004268:DNA-Binding Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D051560:Proto-Oncogene Proteins c-bcl-6; D048008:TNF Receptor-Associated Factor 3; D000097782:NF-kappaB-Inducing Kinase; C490010:Bcl6 protein, mouse