Alteration of BIRC3 and multiple other NF-κB pathway genes in splenic marginal zone lymphoma

Author:

Rossi Davide1,Deaglio Silvia2,Dominguez-Sola David3,Rasi Silvia1,Vaisitti Tiziana2,Agostinelli Claudio4,Spina Valeria1,Bruscaggin Alessio1,Monti Sara1,Cerri Michaela1,Cresta Stefania1,Fangazio Marco1,Arcaini Luca5,Lucioni Marco6,Marasca Roberto7,Thieblemont Catherine8,Capello Daniela1,Facchetti Fabio9,Kwee Ivo10,Pileri Stefano A.4,Foà Robin11,Bertoni Francesco10,Dalla-Favera Riccardo31213,Pasqualucci Laura31214,Gaidano Gianluca1

Affiliation:

1. Division of Hematology, Department of Clinical and Experimental Medicine, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy;

2. Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy;

3. Institute for Cancer Genetics and the Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY;

4. Haematopathology, Department L. & A. Seragnoli, University of Bologna, Bologna, Italy;

5. Divisions of Hematology and

6. Pathology, University of Pavia Medical School, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy;

7. Division of Hematology, Department of Oncology and Hematology, University of Modena and Reggio Emilia, Modena, Italy;

8. Service d'Hémato-Oncologie, Hôpital Saint-Louis, Université Paris Diderot, Paris, France;

9. Divisions of Pathology, Spedali Civili di Brescia, Brescia, Italy;

10. Laboratory of Experimental Oncology and Lymphoma Unit, Oncology Institute of Southern Switzerland (IOSI), Bellinzona, Switzerland;

11. Division of Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy;

12. Departments of Pathology & Cell Biology and

13. Genetics & Development, Columbia University, New York, NY; and

14. Institute of Hematology, University of Perugia, Perugia, Italy

Abstract

Abstract Splenic marginal zone lymphoma (SMZL) is one of the few B-cell lymphoma types that remain orphan of molecular lesions in cancer-related genes. Detection of active NF-κB signaling in 14 (58%) of 24 SMZLs prompted the investigation of NF-κB molecular alterations in 101 SMZLs. Mutations and copy number abnormalities of NF-κB genes occurred in 36 (36%) of 101 SMZLs and targeted both canonical (TNFAIP3 and IKBKB) and noncanonical (BIRC3, TRAF3, MAP3K14) NF-κB pathways. Most alterations were mutually exclusive, documenting the existence of multiple independent mechanisms affecting NF-κB in SMZL. BIRC3 inactivation in SMZL recurred because of somatic mutations that disrupted the same RING domain that in extranodal marginal zone lymphoma is removed by the t(11;18) translocation, which points to BIRC3 disruption as a common mechanism across marginal zone B-cell lymphomagenesis. Genetic lesions of NF-κB provide a molecular basis for the pathogenesis of more than 30% of SMZLs and offer a suitable target for NF-κB therapeutic approaches in this lymphoma.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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