title: Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.
abstract: To interrogate signaling pathways activated in mantle cell lymphoma (MCL) in vivo, we contrasted gene expression profiles of 55 tumor samples isolated from blood and lymph nodes from 43 previously untreated patients with active disease. In addition to lymph nodes, MCL often involves blood, bone marrow, and spleen and is incurable for most patients. Recently, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrated important clinical activity in MCL. However, the role of specific signaling pathways in the lymphomagenesis of MCL and the biologic basis for ibrutinib sensitivity of these tumors are unknown. Here, we demonstrate activation of B-cell receptor (BCR) and canonical NF-κB signaling specifically in MCL cells in the lymph node. Quantification of BCR signaling strength, reflected in the expression of BCR regulated genes, identified a subset of patients with inferior survival after cytotoxic therapy. Tumor proliferation was highest in the lymph node and correlated with the degree of BCR activation. A subset of leukemic tumors showed active BCR and NF-κB signaling apparently independent of microenvironmental support. In one of these samples, we identified a novel somatic mutation in RELA (E39Q). This sample was resistant to ibrutinib-mediated inhibition of NF-κB and apoptosis. In addition, we identified germ line variants in genes encoding regulators of the BCR and NF-κB pathway previously implicated in lymphomagenesis. In conclusion, BCR signaling, activated in the lymph node microenvironment in vivo, appears to promote tumor proliferation and survival and may explain the sensitivity of this lymphoma to BTK inhibitors.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD; Section of Hematology and Medical Oncology, Department of Medicine, Tulane University, New Orleans, LA;
authors.forename: Nakhle S
authors.initials: NS
authors.lastname: Saba
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Delong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Sarah E M
authors.initials: SE
authors.lastname: Herman
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Chingiz
authors.initials: C
authors.lastname: Underbayev
authors.affiliation: Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Xin
authors.initials: X
authors.lastname: Tian
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: David
authors.initials: D
authors.lastname: Behrend
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Marc A
authors.initials: MA
authors.lastname: Weniger
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Martin
authors.initials: M
authors.lastname: Skarzynski
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Jennifer
authors.initials: J
authors.lastname: Gyamfi
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Lorena
authors.initials: L
authors.lastname: Fontan
authors.affiliation: Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY;
authors.forename: Ari
authors.identifier: 0000-0002-8074-2287
authors.initials: A
authors.lastname: Melnick
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Cliona
authors.initials: C
authors.lastname: Grant
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Mark
authors.initials: M
authors.lastname: Roschewski
authors.affiliation: Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Beà
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Kieron
authors.initials: K
authors.lastname: Dunleavy
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Wyndham H
authors.initials: WH
authors.lastname: Wilson
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Adrian
authors.initials: A
authors.lastname: Wiestner
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D019943:Amino Acid Substitution; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D020125:Mutation, Missense; D010880:Piperidines; D011720:Pyrazoles / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D015996:Survival Rate; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C498143:RELA protein, human; D011947:Receptors, Antigen, B-Cell; D051996:Transcription Factor RelA; C551803:ibrutinib; D000225:Adenine