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Blood. 2016 Jul 7;128(1):82-92. doi: 10.1182/blood-2015-11-681460. Epub 2016 Apr 28.

Pathogenic role of B-cell receptor signaling and canonical NF-κB activation in mantle cell lymphoma.

Author information

1
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;
2
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
3
Office of Biostatistics Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;
4
Division of Hematology and Medical Oncology, Department of Medicine, Weill Cornell Medical College, New York, NY;
5
Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
6
Institut d'Investigacions Biomediques August Pi i Sunyer, Barcelona, Spain; and.
7
Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD.

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.

PMID:
27127301
PMCID:
PMC4937360
DOI:
10.1182/blood-2015-11-681460
[Indexed for MEDLINE]
Free PMC Article

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