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Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):766-777
Non-Hodgkin Lymphoma
TIRAP p.R81C is a novel lymphoma risk variant which enhances cell proliferation via NF-kB mediated signaling in B-cells
Regula Burkhard,1,2,3 Irene Keller,4 Miroslav Arambasic,1,2,3 Darius Juskevicius,5 Alexandar Tzankov,5 Pontus Lundberg,6 Rémy Bruggmann,4 Stephan Dirnhofer,5 Ramin Radpour1,7* and Urban Novak1,3*
*RR and UN are co-senior authors.
ABSTRACT
Diffuse large B-cell lymphoma is the most common malignant lymphoma in adults. By gene-expression profiling, this lym- phoma is divided in three cell-of-origin subtypes with distinct molecular and clinical features. Most lymphomas arise sporadically, yet familial clustering is known, suggesting a genetic contribution to disease risk. Familial lymphoma cases are a valuable tool to investigate risk genes. We studied a Swiss/Japanese family with 2 sisters affected by a primary mediastinal B-cell lymphoma and a non-germinal center diffuse large B-cell lymphoma not otherwise specified, respectively. The somat- ic landscape of both lymphomas was marked by alterations affecting multiple components of the JAK-STAT pathway. Consequently, this pathway was constitutively activated as evidenced by high pJAK2 as well as increased nuclear pSTAT3 and pSTAT6 in malignant cells. Potential lymphoma risk variants were identified by whole exome sequencing of the germline DNA derived from siblings and unaffected family members. This analysis revealed a pathogenic variant in TIRAP, an upstream regulator of NF-kB, in both affected siblings and their mother. We observed increased B-cell proliferation in family members harboring the TIRAP p.R81C variant. B-cell proliferation correlated with TIRAP and NF-kB target gene expression, suggesting enhanced NF-kB pathway activity in TIRAP p.R81C individuals. TIRAP knockdown reduced B-cell survival and NF-kB target gene expression, particularly in individuals with TIRAP p.R81C. Functional studies revealed significant- ly increased NF-kB activity and resistance to stress-induced cell-death by TIRAP p.R81C. The identification of an inherited TIRAP variant pro- vides evidence for a novel link between genetic alterations affecting the NF-kB pathway and lymphomagenesis.
Introduction
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adults.1 Its molecular subtypes, activated B-cell-like (ABC), germinal center B-cell- like (GCB) DLBCL, and primary mediastinal B-cell lymphoma (PMBL) arise from B-cells at distinct differentiation stages.2,3 PMBL is clinically aggressive with bulky mediastinal masses; it accounts for up to 10% of DLBCLs, and preferentially occurs in young female patients.
Next-generation sequencing provided insights in genetic lesions of de novo DLBCL and its subtypes.4-10 The genetic hallmarks of PBML are amplifications of the 9p24 locus containing JAK2 and PDL1. Present in 70% of PMBL, this amplification is rare in other DLBCL subtypes.11-13 Constitutive NF-kB pathway activity through various mechanisms is characteristic of PMBL and ABC-DLBCL.14
1Department of Medical Oncology, Inselspital, Bern University Hospital; 2Division of Experimental Pathology, Institute of Pathology, University of Bern; 3Department for BioMedical Research (DBMR), University of Bern; 4Interfaculty Bioinformatics Unit, Department for BioMedical Research, and Swiss Institute of Bioinformatics, University of Bern; 5Institute of Pathology and Medical Genetics, University of Basel; 6Department of Biomedicine, Experimental Hematology, University Hospital Basel and University of Basel and 7Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Switzerland
Until now, the genetic risk factors for DLBCL/PMBLs have remained obscure.
Correspondence:
URBAN NOVAK
urban.novak@insel.ch
Received: August 9, 2018. Accepted: October 30, 2018. Pre-published: October 31, 2018.
doi:10.3324/haematol.2018.201590
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/766
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